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Biomedical subjects

R F Williams

Publications and source records attributed to R F Williams.

At least 73 records · Page 4Linked to original sources
PubMed1989

Probing studies on multiple dose effects of antide (Nal-Lys) GnRH antagonist in ovariectomized monkeys.

This study was designed to extend evaluation of the long-acting effects of a "third generation" Antide (Nal-Lys) GnRH antagonist on gonadotropin secretion in ovariectomized (OVX) monkeys, with special attention to recrudescence of pituitary gonadotropin secretion after multiple dose treatments, as well as pituitary secretory responsiveness to GnRH. The duration of FSH/LH inhibition by Antide was dose-dependent, as well as being much longer than for Nal-Glu GnRHant; however, full recrudescence of gonadotropin secretion, albeit gradual, did occur. The acute LH secretory response to serial iv boluses of GnRH, in the face of GnRHant-induced suppression of gonadotropin secretion, was transiently accelerated and biologically active. Thereafter, the state of FSH/LH inhibition was resumed chronically. Thus, treatment with Antide produced profound long-term inhibition of tonic gonadotropin levels, yet hyper-responsiveness to exogenous GnRH administration was maintained throughout.

Animals↗
PubMed1989

RU 486 mediated leukocytic inflammatory reaction at the utero-placental interface.

Placentae obtained from RU 486 treated cynomolgus monkeys, with successful pregnancy outcome, could not be distinguished, by microscopic or macroscopic examination, from normal placental morphology of untreated females. However, circulating PAPP-A levels were markedly depressed in RU 486 treated (114.8 +/- 13.1 IU/l) than in control animals (477.2 +/- 150 IU/l), suggesting compromised placental physiology. Microscopic examination of placental tissue obtained from animals with fetal demise, after RU 486 administration, revealed pathological changes. When fetal demise occurred recently (less than 24 h), active villus destruction by infiltrating polymorphonuclear leukocytes was readily observed. Whereas aqueous extracts of placentae, whether obtained by cesarean section or spontaneous delivery, inhibited neutrophil elastase (HGE) activity, extracts of placenta being degraded by host phagocytic-proteolytic defense system were rich in HGE activity. Thus suggesting that parturition was not mediated by leukocyte lysosomal proteases, such as HGE, and that hemochorrially implanted placentae produce PAPP-A, a specific inhibitor of HGE. Administration of RU 486 decreased placental PAPP-A production and secretion, culminating with a neutrophilic infiltration into placental intervillous blood spaces, destruction of villus structure and fetal demise.

Animals↗
PubMed1988

Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist.

The dose-response effects of a single administration of Nal-Lys-GnRHant (antagonist) on serum LH and FSH concentrations were compared to the effects of Nal-Glu-GnRHant in monkeys. Twenty ovariectomized monkeys were divided into four sc treatment groups: a) 1.0 mg/kg Nal-Glu-GnRHant; or Nal-Lys-GnRHant at b) 0.3; c) 1.0; d) 3.0 mg/kg. Each monkey received vehicle (propylene glycol/water, 1:1) on day 0, followed by an antagonist preparation on day 11. Serum LH and FSH were measured by RIA; serum LH was also measured by in vitro bioassay. The short-term effects were similar among the four treatment groups. Typically, serum LH declined (p less than 0.05) within 4 to 8 h, achieving maximal reduction by 24 h. Serum FSH levels declined more slowly, but were significantly reduced by 24 h (p less than 0.05). Recovery during the study interval to pretreatment control values occurred in only two groups: a) Nal-Glu-GnRHant (1.0 mg/kg) by day 4 post-treatment and b) Nal-Lys-GnRHant (0.3 mg/kg) by day 2 post-treatment. Monkeys receiving 1.0 or 3.0 mg/kg Nal-Lys-GnRHant had a prolonged inhibition of serum LH and FSH levels. In all animals, serum FSH and LH returned to control levels within 2 months. The duration of gonadotropin inhibition was also prolonged when the Nal-Lys-GnRHant was administered iv. In contrast, Nal-Glu-GnRHant reduced serum LH and FSH for 3 days or less in all monkeys. The serum bioassayable LH levels paralleled those of immunoassayable LH. The prolonged inhibition of gonadotropin secretion following Nal-Lys-GnRHant distinguishes its action from those of previous GnRH antagonists and make this compound of great interest for clinical investigations.

Animals↗
PubMed1987

Effect of pregnancy on surgically induced endometriosis in cynomolgus monkeys.

There are few objective data to support the clinical impression that pregnancy exerts a beneficial effect on endometriosis. In this study, we examined the progression-regression of endometriosis in pregnant and nonpregnant monkeys. Endometriosis was surgically induced in 16 monkeys and classified as minimal (n = 5), mild (n = 5), moderate (n = 4), or severe (n = 2). Monkeys were mated and pregnancy occurred in three monkeys with minimal, three with mild, and one with moderate endometriosis. Laparotomy was performed to stage the disease and to obtain biopsy specimens of implants 1 month post partum or 6 to 8 months after initial operation in nonpregnant monkeys. Monkeys with minimal and mild disease had complete regression of macroscopic disease. Histologic examination of the implants showed only fibrosis and hemosiderin deposits, except in one animal with mild endometriosis containing microscopic foci of endometrial glands. The one monkey with moderate disease had significant, but not complete regression of implants. Endometriosis in nonpregnant monkeys tended to progress. These findings demonstrate that pregnancy does exert a beneficial effect on endometriosis and suggest that pregnancy commonly results in complete resolution of minimal or mild disease.

Animals↗
PubMed1987

Receptivity to persons with mental retardation: a study of volunteer interest.

College students (N = 78) completed a series of questionnaires dealing with their personal value systems, perceptions and attitudes concerning persons with mental retardation, volunteer experience, and attitudes and beliefs regarding volunteer work with persons with mental retardation. They were then questioned as to their interest in doing such volunteer work. Data on the students who expressed an interest in volunteer work and those who did not were compared. Results showed that the importance that students placed on certain values in their personal lives was the best predictor of volunteer interest. The importance of these findings for better understanding the nature of people's receptivity to persons with mental retardation was discussed.

Adult↗
PubMed1986

Histologic and hormonal documentation of the luteinized unruptured follicle syndrome.

Histologic and hormonal documentation of a luteinized unruptured follicle that occurred during a spontaneous menstrual cycle in a rhesus monkey is presented. Frequent (every 2 hours) blood sampling to assess midcycle hormonal dynamics in the monkey with the luteinized unruptured follicle and in five monkeys with an ovulatory stigma revealed significant aberrations in the gonadotropin and steroid hormone profiles associated with a luteinized unruptured follicle. Although the midcycle 17 beta-estradiol surge was normal, the monkey with the luteinized unruptured follicle demonstrated (1) blunted midcycle bioassayable luteinizing hormone, immunoassayable luteinizing hormone, and follicle-stimulating hormone surges; (2) absence of disparity in the bioassayable luteinizing hormone: immunoassayable luteinizing hormone ratio during the gonadotropin surge; (3) absence of progesterone and 17 alpha-hydroxyprogesterone secretion during the gonadotropin surge; and (4) delayed and blunted rise in progesterone and 17 alpha-hydroxyprogesterone after the gonadotropin surge. These findings suggest that an impaired luteinizing hormone surge, perhaps mediated by insufficient midcycle progestin secretion, is one possible cause of the luteinized unruptured follicle syndrome.

17-alpha-Hydroxyprogesterone↗
PubMed1986

Prevention of gonadotropin-releasing hormone antagonist induced luteal regression by concurrent exogenous pulsatile gonadotropin administration in monkeys.

We studied the effects of a gonadotropin-releasing hormone (GnRH) antagonist given in midluteal phase. Monkeys received the antagonist (n = 6), [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-GnRH: hydrochloride or vehicle (n = 5). Absent luteinizing hormone (LH) pulsatility, diminished progesterone (P) secretion (P less than 0.01), luteal phase truncation and premature menstruation were observed in all receiving the antagonist. To investigate the site of action, four females received pulsatile exogenous human menopausal gonadotropins (hMG) concurrently, whereby P secretion was sustained and premature menstruation was averted. Equivalent treatment using "pure" FSH, failed to sustain P levels and timely menstruation occurred, confirming the continuing dependence of the corpus luteum on LH. The antagonist acts by central suppression and in turn, diminishes P biosynthesis. LH is luteotropic, since pulsatile LH (hMG), not "pure" FSH, prevented luteolysis.

Animals↗
PubMed1985

A photoaffinity derivative of colchicine: 6'-(4'-azido-2'-nitrophenylamino)hexanoyldeacetylcolchicine. Photolabeling and location of the colchicine-binding site on the alpha-subunit of tubulin.

A photoaffinity analog of colchicine, 6-(4'-azido-2'-nitrophenylamino)hexanoyldeacetylcolchicine, was synthesized by reacting deacetylcolchicine or [3H]deacetylcochicine with N-succinimidyl-6-(4'-azido-2'-nitrophenylamino)hexanoate. Homogeneity of the photoaffinity analog was established by thin-layer chromatography and high-pressure liquid chromatography. The structure of the photoaffinity analog was determined by 1H and 13C NMR, infrared and ultraviolet-visible spectroscopies, and elemental analysis. Binding of 6-(4'-azido-2'-nitrophenylamino)hexanoyldeacetylcolchicine to bovine renal tubulin was measured by competition with [3H]colchicine. The value of the apparent Ki for the photoaffinity analog was 0.28 microM in the concentration range of 0.8-1.2 microM of the analog. A value of 0.50 microM for the apparent Kd was measured by the direct binding of the tritiated photoaffinity analog to tubulin. The analog is slightly more potent an inhibitor of microtubule formation than colchicine. The photoaffinity analog reacted with renal tubulin upon irradiation with a mercury lamp equipped with a 420-nm cutoff filter. Spectral and radiochemical analyses of the tubulin after photolysis and dialysis have demonstrated a stoichiometric incorporation of the photoaffinity analog in the alpha-subunit of the tubulin. Covalent labeling of tubulin with the photoaffinity analog decreases the extent of [3H]colchicine binding by more than 90%.

Affinity Labels↗
PubMed1985

Lactational amenorrhea in monkeys: effects of suckling on prolactin secretion.

To determine the acute and chronic effects of suckling on maternal PRL secretion in monkeys, five mother-infant pairs were studied longitudinally on days 40, 80, 120, and 10 after weaning (day 160). Mothers were chronically cannulated and, during blood collections, wore protective nylon vests with mobile tethers. Studies were undertaken during the day and night with the mother and infant undisturbed, during the daytime, before and after the removal of the infant, and during the day and night before and after the reunion of mother and infant. Maternal PRL levels were significantly (P less than 0.05) higher at night than during the day in undisturbed mother-infant pairs. This nocturnal elevation was probably induced by a more intensive interaction of the mother and infant at night than during the day. Basal PRL concentrations in samples collected during these undisturbed settings significantly (P less than 0.05) declined as the postpartum interval continued. The removal of the infant did not perturb maternal PRL patterns. Typically, after reunion of mother and infant, maternal PRL levels were increased significantly (P less than 0.05), reaching maximal levels approximately 2 h after reunion. If PRL secretion, induced by the suckling stimulus, is instrumental in sustaining puerperal infertility, then the increased secretion of PRL that occurs at night during the protracted interval of intense mother-infant interaction may be of particular significance in inhibition of the hypothalamic-pituitary-ovarian axis.

Amenorrhea↗
PubMed1985

Hyperprolactinemia induced by an estrogen-progesterone synergy: quantitative and temporal effects of estrogen priming in monkeys.

We evaluated the quantitative and temporal characteristics of the estrogen component of an estrogen-progesterone synergy, which can induce hyperprolactinemia in macaques. In Exp I, six groups of monkeys were treated for 2 weeks with various doses of estradiol benzoate (EB), which resulted in peripheral estradiol concentrations of 250-1500 pg/ml, followed by 2 weeks of combined estrogen and progesterone treatment. In each of the groups, regardless of the dosages of estradiol benzoate alone, PRL concentrations remained within normal limits (approximately 18 ng/ml). In contrast, during the subsequent period of combined EB and progesterone therapy, hyperprolactinemia developed. The resultant PRL concentrations were not dependent on the dose of EB administered. In Exp II, three groups of monkeys were treated with EB (25 micrograms/kg) alone for various intervals and subsequently with both EB and progesterone for 14 days. When initiation of progesterone therapy was preceded by a 9- or 6-day period of estrogen priming, PRL concentrations were significantly (P less than 0.05) elevated within 3-4 days; in contrast, when the EB and progesterone treatments were initiated simultaneously, 8 days elapsed before the PRL elevations were significant. In a third experiment, to determine whether decidualized endometrium accounted for the increased PRL levels following estrogen and progesterone treatment, a hysterectomized monkey was treated with EB followed by combined EB and progesterone treatment. The PRL response was not different from that of intact monkeys similarly treated. From these findings we conclude 1) that the estrogen-progesterone synergy promoting PRL secretion is not of endometrial origin; 2) that approximately 1 week of estrogen priming is required for progesterone to induce PRL secretion; 3) and that the mode of action of estrogen is not dose dependent, but, rather, is a threshold effect.

Animals↗
PubMed1985

Periovulatory hormonal dynamics: relationship of immunoassayable gonadotropins and ovarian steroids to the bioassayable luteinizing hormone surge in rhesus monkeys.

The relationship between ovarian steroids and LH during the midcycle gonadotropin surge is controversial. Recent demonstration of temporal and quantitative differences in immunoassayable LH (I-LH) and bioassayable LH (B-LH) at midcycle have further clouded this issue. To evaluate the relationship of I-LH, FSH, and ovarian steroids to the onset of the midcycle B-LH surge, blood samples were obtained from five chronically catheterized rhesus monkeys at 2-h intervals for 5-6 days. The plasma was assayed for FSH, LH, 17 beta-estradiol (E2), progesterone (P4), and 17 alpha-hydroxyprogesterone (17-OHP) by RIA and for LH by a rat interstitial cell testosterone in vitro bioassay. The initiation of the B-LH surge served as time zero (to) for the temporal analysis of changes in plasma hormone levels. The I-LH and FSH surges were initiated 6.4 +/- 2.2 h (mean +/- SEM) and 5.2 +/- 1.9 h, respectively, after the onset of the B-LH surge. Although the duration of the ascending limb of the surge was similar for B-LH, I-LH, and FSH, the mean +/- SEM total duration of the B-LH surge (34.5 +/- 3.5 h) was significantly longer (P less than 0.025) than those of I-LH (24.4 +/- 5.0 h) and FSH (27.6 +/- 2.3 h). Before the onset of the B-LH surge (to - 4 h), the ratio of B-H to I-LH was unity; however, during the acme of gonadotropin secretion (to + 12-16 h), the B-LH to I-LH ratio approached 6:1. Doubling times for B-LH, I-LH, and FSH were similar during the ascending phase of the surge. Plasma E2 concentrations increased continuously from to - 40 h to to, with a mean +/- SEM doubling time of 32.6 +/- 4.7 h. Peak E2 concentrations occurred within 6 h after the onset of the B-LH surge. Plasma P4 concentrations began to increase at to - 6 h in four monkeys and at to in one monkey. Plasma P4 concentration plateaued from to to to + 24 h, then increased rapidly, with a mean +/- SEM doubling time of 20.5 +/- 2.9 h. Although there were significant individual variations in plasma 17-OHP concentrations, a definite increase in 17-OHP occurred by to - 10 h, and peak concentrations occurred at to + 1 h.(ABSTRACT TRUNCATED AT 400 WORDS)

17-alpha-Hydroxyprogesterone↗
PubMed1985

Progesterone and 17 alpha-hydroxyprogesterone advance the estrogen-induced bioassayable luteinizing hormone surge in castrate monkeys.

Recent studies have demonstrated marked disparities between bioassayable (BIO) versus radioimmunoassayable concentrations of luteinizing hormone (LH) at midcycle. Other studies in intact women and monkeys have indicated that progesterone (P) may facilitate estrogen induction of the preovulatory gonadotropin surges. We have combined the study of these observations as follows: long-term castrate female monkeys were given estradiol benzoate with and without subsequent P or 17 alpha-hydroxyprogesterone (17-OHP) injections. Plasma was collected during a selected 24-hour interval via a chronic indwelling femoral vein cannula. Initially, estrogen-negative feedback decreased the pulsatility and circulating levels of gonadotropins. P and 17-OHP treatment (after estradiol) hastened initiation of the BIO-LH surge by up to 8 hours. Although estrogen-positive feedback alone enhanced the biologic activity of LH, P and 17-OHP expedited the midcycle-like BIO-LH surges.

17-alpha-Hydroxyprogesterone↗
PubMed1984

Etiology of infertility in monkeys with endometriosis: measurement of peritoneal fluid prostaglandins.

To study the relationship between peritoneal fluid prostaglandins and infertility associated with endometriosis, we autografted endometrial or adipose tissue to the pelvic peritoneum in 21 monkeys. Peritoneal washings were collected prior to tissue transplantation and during a subsequent laparotomy performed for biopsy of the implants. Monkeys were mated and peritoneal washings were collected during three subsequent cycles. The content of prostaglandin F2 alpha (PGF2 alpha) in adipose tissue autografts was significantly less (p less than 0.05) than in endometrial tissue autografts. The PGF2 alpha concentration in peritoneal fluid increased significantly (p less than 0.05) only in monkeys that developed moderate or severe endometriosis. Prostaglandin E levels in tissue autografts or peritoneal fluid were similar in all animals. Infertility in monkeys with endometriosis was associated with luteinized unruptured follicles, luteal phase defects, and pelvic adhesions. Although PGF2 alpha concentrations in peritoneal washings obtained during these cycles were increased in comparison with those of ovulatory cycles, the difference was not significant. A relationship between spontaneous abortion and prostaglandin concentrations in peritoneal fluid was not established.

Animals↗
PubMed1984

Electrophoresis of proteins and nucleic acids on acrylamide-agarose gels lacking covalent crosslinking.

The preparation of acrylamide-agarose gels lacking covalent crosslinking with methylenebisacrylamide is described. These hybrid gels melt at 85 degrees C and, consequently, allow quantitative analysis of tritium-labeled protein after electrophoresis. Recovery of tritium-labeled ribonucleic acids extracted from hybrid gels is 20 to 25% greater than from standard acrylamide-methylenebisacrylamide gels. Standard curves of electrophoretic mobilities as a function of molecular weights of dissociated proteins and ribonucleic acids are compared for acrylamide-agarose gels and acrylamide-methylenebisacrylamide gels.

Electrophoresis, Agar Gel↗
PubMed1984

Pulsatile progesterone secretion: its relevance to clinical evaluation of corpus luteum function.

Pulsatile progesterone (P) secretory patterns were characterized in rhesus macaques (n = 13) during the midluteal phase (cycle days 18 to 20) of the normal ovarian/menstrual cycle. Sixty high-amplitude (greater than 1 ng/ml) P pulses were observed during a total of 169 hours of sampling. Typically, P pulses had an ultradian periodicity of 2 hours and were independent of detectable luteinizing hormone (LH) and prolactin (PRL) pulses in 70% of instances. LH pulses were associated with a concomitant P and PRL pulse in 100% to 80% of occasions, respectively. Pulsatile P release was augmented by exogenous cynomolgus monkey LH and suppressed by administration of a gonadotropin-releasing hormone antagonist. Two individuals with apparently normal ovulation and once daily plasma P concentrations within the normal range demonstrated a nonpulsatile P profile. These findings encourage clinical investigations to characterize pulsatile P secretion in normal women and patients in whom corpus luteum dysfunction is suspected.

Animals↗