Hypogonadotropic hypogonadism: hormonal responses to low dose pulsatile administration of gonadotropin-releasing hormone

Patients with isolated gonadotropin deficiency were studied to determine whether pulsatile low dose gonadotropin-releasing hormone (GnRH) could induce the hormonal changes seen during normal puberty. Four male and two female patients with immature responses to a standard GnRH test (2.5 micrograms/kg) were given GnRH (0.025 micrograms/kg) iv every 2 h for 5 days. FSH responses varied between the sexes, and FSH concentrations in males rose continuously to 17.2 +/- 4.7 mIU/ml on day 5. In the females, FSH peaked at 13.8 and 15.8 mIU/ml on days 3-4 and then declined. The males showed increasing and the females decreasing incremental FSH responses to GnRH. LH concentrations and incremental responses to GnRH rose throughout the study in both sexes. Plasma testosterone rose slightly in the males to 0.7 +/- 0.2 ng/ml (P < 0.05), but in females estradiol increased to follicular range concentrations of 128 and 102 pg/ml. Standard GnRh tests on day 6 revealed maturation of gonadotropin responses in all patients. After termination of pulsatile GnRH, four patients were given single low dose GnRH injections on two to seven occasions over a period of 2-32 days. Initial LH responses were 2- to 14-fold greater than those seen on day 5 of pulsatile GnRH, and decreased over the next 3 weeks. FSH responses showed less initial augmentation and declined more slowly. Low dose pulsatile administration of GnRH to patients with isolated gonadotropin deficiency results in changing patterns of hormone secretion similar to those seen during puberty. Exaggerated pituitary sensitivity to GnRH may be present long after a brief period of GnRH stimulation, and may indicate previous rather than current secretion of GnRH.     

A daily neural signal for luteinizing hormone release in the untreated ovariectomized rat: changes in gonadotropin-releasing hormone content of the preoptic area and hypothalamus throughout the day.

Gonadotropin-releasing hormone (GnRH) content of preoptic areas (POA) and hypothalami, and serum gonadotropins of rats ovariectomized six weeks earlier were measured throughout the day in two experiments. In the first, rats were decapitated at 2 h intervals between 0800 and 1800 h. The entire preoptic-hypothalamic region was removed and extracted for radioimmunoassay (RIA) of GnRH. Serum gonadotropins measured by RIA were highly variable but mean concentrations were not significantly different throughout the day. However, preoptic hypothalamic content of GnRH declined markedly between 1000 and 1200 h. In the second experiment, 75 rats were divided into three groups and were untreated or were implanted sc with empty Silastic capsules or capsules containing estradiol-17beta (E2). Two days later, groups of five rats from each of the three treatment groups were decapitated at 0800, 1100, 1400, 1700 and 2000 h. The preoptic area was separated from the hypothalamus by a transverse cut at the caudal aspect of the optic chiasm. POA and hypothalamic content of GnRH correlated well (r=0.74, P less than 0.001, n=75). Two-way analysis of variance failed to reveal any effect of treatment on the GnRH content in either the POA or hypothalamus. GnRH content of both regions decreased significantly between 1100 and 1700h regardless of whether E2 was administered. In striking contrast, gonadotropin surges occurred in the late afternoon only in the E2-treated rats. Serum GnRH was undetectable (less than 5 pg/ml) in all groups of animals. These experiments demonstrate that in the untreated ovariectomized rat GnRH content of the POA and hypothalamus decreases during the early afternoon. This study supports the concent of a daily neural signal for LH release and that E2 is necessary for expression of the daily LH surge in the ovariectomized rat.     

Polymeric triple-shape materials

Shape-memory polymers represent a promising class of materials that can move from one shape to another in response to a stimulus such as heat. Thus far, these systems are dual-shape materials. Here, we report a triple-shape polymer able to change from a first shape (A) to a second shape (B) and from there to a third shape (C). Shapes B and C are recalled by subsequent temperature increases. Whereas shapes A and B are fixed by physical cross-links, shape C is defined by covalent cross-links established during network formation. The triple-shape effect is a general concept that requires the application of a two-step programming process to suitable polymers and can be realized for various polymer networks whose molecular structure allows formation of at least two separated domains providing pronounced physical cross-links. These domains can act as the switches, which are used in the two-step programming process for temporarily fixing shapes A and B. It is demonstrated that different combinations of shapes A and B for a polymer network in a given shape C can be obtained by adjusting specific parameters of the programming process. Dual-shape materials have already found various applications. However, as later discussed and illustrated by two examples, the ability to induce two shape changes that are not limited to be unidirectional rather than one could potentially offer unique opportunities, such as in medical devices or fasteners.     

Low dose pulsatile gonadotropin-releasing hormone in anorexia nervosa: a model of human pubertal development.

Patients suffering from anorexia nervosa were studied to determine whether gonadotropin-releasing hormone (GnRH) could induce the hormonal changes which occur during normal puberty. Three amenorrheic patients were studied at low body weight (less than 70% ideal BW). All three patients were prepubertal, as evidenced by immature LH and FSH responses to a standard GnRH test (2.5 micrograms/kg BW) and the absence of spontaneous LH peaks both during the day and during sleep. Low doses of GnRH (0.025--0.05 microgram/kg), aimed at producing peak plasma GnRH values of approximately 200 pg/ml, were given by iv bolus injection every 2 h for 5 days. Plasma responses of FSH, LH, and estradiol were measured by RIA. Preinjected FSH values rose rapidly to plateau (range, 15--30 mIU/ml) on the second to third day before falling despite the continued administration of GnRH. In contrast, plasma LH and estradiol increased gradually throughout the 5 days of injections. Acute FSH responses to GnRH initially exceeded those of LH but subsequently decreased, whereas LH increments increased progressively after the first 36 h of injections. The 5 days of low dose GnRH pulses induced maturation of the hormone responses to the standard GnRH test, so that LH release exceeded that of FSH at the completion of the study. These changes in the patterns of FSH and LH secretion are similar to those seen during normal puberty in girls and during the follicular phase of the menstrual cycle. The results demonstrate a changing pattern of pituitary response to physiological administration of GnRH and indicate that the changes in gonadotropin secretion during normal puberty are consistent with the effects of the single decapeptide GnRH.     

Modulation of serum follicle-stimulating hormone bioactivity and isoform distribution by estrogenic steroids in normal women and in gonadal dysgenesis

To determine the influence of estrogenic steroids on serum FSH bioactivity (B) and immunoreactivity (I) and the FSH isoform distribution profiles, we studied normal women during ovulatory menstrual cycles and a patient with gonadal dysgenesis treated with diethylstilbestrol (DES). Four women with ovulatory menstrual cycles, as judged from their serum immunoreactive LH, FSH, progesterone, and estradiol profiles in daily blood samples, had a significant increase in the mean FSH B/I ratio (P less than 0.05) during the midcycle phase of their menstrual cycles. Similarly, in the patient with gonadal dysgenesis the FSH B/I ratio rose significantly (P less than 0.05) after 3 weeks of DES treatment and declined during the posttreatment period. In five additional normal women, serum obtained during the follicular, midcycle, and luteal phases of their menstrual cycles was chromatofocused, and the FSH isoform distribution pattern determined. Sera obtained from the patient with gonadal dysgenesis before, during, and after DES administration were pooled and studied similarly. Chromatofocusing of a human pituitary tumor extract allowed for determination of the FSH B/I ratio in different pH ranges. The highest FSH B/I ratio was found in the more basic fractions (pH range 5.6-6.0) compared to the acidic fractions. During both the midcycle phase of the normal cycles and the DES administration period in the studies of the patient with gonadal dysgenesis, there was a shift of the FSH isoforms (as measured by immunoassay) to the basic pH range. In contrast, the mid- to late luteal phase samples, which had low B/I ratios, had an increase in FSH isoforms in the acidic pH range (less than 4.8). Similarly, in the patient with gonadal dysgenesis FSH isoforms in the basic range were more abundant during the DES treatment period than in the pre- or posttreatment serum pools. Therefore, it appears that endogenous and exogenous estrogenic stimulation alters FSH isoform distribution such that FSH isoforms that are more basic and have increased biological activity are secreted.     

The roles of estradiol and progesterone in decreasing luteinizing hormone pulse frequency in the luteal phase of the menstrual cycle

During the luteal phase of the menstrual cycle, plasma progesterone (P) and estradiol (E2) concentrations are elevated, and LH (and by inference GnRH) pulse frequency is slow. In contrast, LH pulse frequency increases during the early follicular phase when plasma E2 and P are lower. To examine the mechanism(s) responsible for the slower GnRH pulse frequency in the luteal phase, we maintained plasma P, E2, or both at midluteal concentrations from the midluteal phase to the time of the next early follicular phase and measured the effects on LH secretion. Thirteen normal women with regular menstrual cycles were studied during two or three cycles. Blood was obtained every 10 min during 10-h studies. Control cycle luteal and early follicular studies were followed by a second control study in the luteal phase of the treatment cycle. P (six women), E2 (seven women), or both (five women) then were given twice daily by im injection for 6-12 days until the day corresponding to the early follicular study of the control cycle (EF + P, EF + E2, or EF + E2 + P). A final study was performed 1 week after the injections were discontinued (F). LH pulse frequency was low in the midluteal phase [3.2 +/- 0.2 (+/- SE) pulses/10 h] and increased by the early follicular phase (8.0 +/- 0.8 pulses/10 h) in the control cycles. The increase in LH pulse frequency was not significantly inhibited by administration of P (6.7 +/- 0.7 pulses/10 h; EF + P). However, during both E2 alone and E2 + P, LH pulse frequency remained low (EF + E2, 3.6 +/- 0.8; EF + E2 + P, 2.0 +/- 0.7 pulses/10 h). The mean plasma FSH concentrations paralleled changes in LH pulse frequency, increasing from the luteal to the early follicular phase in the control cycles and during P injections and remaining low during E2 and E2 + P injections. We conclude that continued exposure to P alone does not maintain GnRH pulse frequency at midluteal phase values and that any effect of P requires the presence of E2. As E2 alone maintained lower LH pulse frequency, E2 may act directly to decrease the pulsatile GnRH secretion or it may potentiate the effects of low (less than 3.2 nmol/L) P concentrations.     

Impact of the material and sintering protocol,layer thickness,and thermomechanical aging on the two-body wear and fracture load of 4Y-TZP crowns

Clinical Oral Investigations - The aim of this study is to investigate the influence of the material and corresponding sintering protocol, layer thickness, and aging on the two-body wear (2BW) and...     

Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease

Polycystic ovarian disease (PCO) is characterized by hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. Mean plasma FSH concentrations are low, while LH is elevated in a majority of patients. LH pulsatile secretion has been shown to occur at rapid follicular phase frequencies (approximately one pulse per h) in PCO, suggesting persistent rapid frequency GnRH secretion in this disorder. Anovulatory women with PCO were given estradiol (E2; Estraderm skin patches) and progesterone (P; vaginal suppositories) to produce midluteal concentrations for 21 days. The aim was to determine if E2 and P would slow LH (GnRH) pulse frequency and if this would result in augmented FSH secretion and follicular development after withdrawal of E2 and P. Plasma LH was measured every 10 min for 8 h before, during (days 10 and 20), and 7 days after withdrawal of E2 and P (day 28). On each of these study days FSH was measured hourly, and E2 and P were measured every 2 h. After sampling, GnRH (25 and 250 ng/kg, iv) was given to assess pituitary responsiveness. Follicular development was monitored by vaginal ultrasound through day 34 of the study. Basal LH frequency was 8.5 +/- 0.5 pulses/8 h (mean +/- SEM). During E2 and P, LH pulse frequency fell to 3.3 +/- 1.0 (10 days) and 2.3 +/- 0.8 (20 days), 39% and 27% of the basal value, respectively, and subsequently increased to 5.6 +/- 0.7 (66% of basal) 7 days after withdrawal of E2 and P. LH pulse amplitude (basal, 7.2 +/- 1.5 IU/L) was not reduced until day 20, but remained suppressed (3.9 +/- 1.1 IU/L) on day 28. As a result, mean LH (basal, 21.0 +/- 3.5 IU/L) fell progressively during E2 and P, to 3.8 +/- 1.2 IU/L on day 20, and remained low (39% of basal) 7 days after steroid withdrawal. Mean plasma FSH (basal, 7.1 +/- 0.9 IU/L) also fell during steroid administration, but in contrast to LH, had risen to 93% of the basal value by 7 days after E2 and P. LH release in response to exogenous GnRH revealed marked initial responses which did not decrease until day 20, but remained suppressed (8% of basal) after withdrawal of E2 and P. FSH responses were also suppressed on day 20, but had increased to 75% of the basal value by day 28. Initiation of follicular development occurred in all patients, and the lead follicle measured 12.3 +/- 0.8 mm 13 days post-E2 and P. Ovulation occurred in one patient.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiological and behavioral responses to starvation in the golden hamster.

Physiological and behavioral responses of adult hamsters to starvation were studied by measuring food intake, weight recovery, serum concentrations of glucose, insulin, free fatty acids and beta-hydroxybutyrate, and ketonuria in animals subjected to different weight losses, diets, and durations of fast. Hamsters were debilitated by fasts longer than 12 h or leading to greater than 20% weight loss. Hamsters' feeding patterns were unmodified by fasts ranging between 5 and 12 h and showed no circadian periodicity. Hamsters predominantly recovered from weight losses without increasing their food consumption (unless they were offered a diet of pellets and seeds) and without changing their meal patterns, at a rate of weight gain proportional to the magnitude of preceding weight loss if provided with uninterrupted access to food. By 8 h of fast, blood metabolites were indicative of mobilization of body fat. Hamsters are thus behaviorally unresponsive to duration of fast, but compensate physiologically for weight losses with proportional increases in the rate of weight gain.