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Biomedical subjects

R F Williams

Publications and source records attributed to R F Williams.

At least 91 records · Page 5Linked to original sources
PubMed1984

Etiology of infertility in monkeys with endometriosis: luteinized unruptured follicles, luteal phase defects, pelvic adhesions, and spontaneous abortions.

To elucidate the etiology of infertility due to endometriosis, we autografted endometrial or adipose tissue to the pelvic peritoneum of 21 cynomolgus monkeys. These primates were divided into five groups: control animals with adipose tissue autografts (n = 5), animals with microscopic endometriosis (n = 5), animals with mild endometriosis (n = 5), animals with moderate endometriosis (n = 4), and animals with severe endometriosis (n = 2). During three subsequent menstrual cycles, each animal underwent (1) serial assay of peripheral serum gonadotropins and steroids; (2) mating timed according to daily serum 17 beta-estradiol; and (3) laparotomy to document an ovulatory stigma. The chemical and term pregnancy rates were lower among monkeys with moderate or severe endometriosis, as compared with control animals. The impaired fertility in monkeys with endometriosis appeared to be mediated primarily by failure of follicular rupture and/or pelvic adhesions.

Abortion, Spontaneous↗
PubMed1984

Ovulation induction using "pure" follicle-stimulating hormone in monkeys.

Recently we have demonstrated that administration of a "pure" follicle-stimulating hormone (FSH) preparation (Urofollitropin, Serono Laboratories, Inc., Randolph, MA) to normally cycling monkeys induces multiple follicular development. In these earlier studies, a spontaneous luteinizing hormone (LH) surge was uncommon; no attempt was made to induce ovulation with exogenous human chorionic gonadotropin (hCG). In this study, multiple follicular development and ovulation were induced in normally cycling monkeys by daily follicular phase administration of "pure" FSH followed by hCG. Short-term administration of "pure" FSH during the early or late follicular phase also induced multiple follicular development; however, multiple ovulations subsequent to a spontaneous LH surge never occurred. One monkey treated in the late follicular phase did demonstrate a spontaneous LH surge and single ovulation following late follicular phase FSH treatment. These findings suggest that administration of "pure" FSH alone, to enhance the natural ovarian cycle, may be useful for inducing multiple follicular development, but that ovulatory competence is usually dependent on exogenous LH/hCG.

Animals↗
PubMed1984

Medical hypophysectomy: II. Variability of ovarian response to gonadotropin therapy.

In an attempt to control individual variability of ovarian response to gonadotropin therapy, ovulatory monkeys received either "pure" follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG), with or without gonadotropin-releasing hormone (GnRH) antagonist administration. Among females that responded to gonadotropin therapy, the GnRH antagonist reduced (P less than 0.05) the variability of serum estradiol patterns. Surprisingly, after pretreatment and concurrent administration of the GnRH antagonist, FSH alone was as effective as the FSH/luteinizing hormone (LH) mixture (hMG) in stimulating follicular maturation, even when serum LH levels were at or below the limits of detection. The results indicate that in a rapidly reversible hypogonadotropic state approaching a "medical hypophysectomy," concurrent gonadotropin therapy produces a less varied ovarian response. The relative (un)importance of LH in the primate ovarian cycle seems diminished in the face of evidence that FSH alone, or in the presence of vanishingly small amounts of LH, supports follicular maturation and dynamic estrogen biosynthesis.

Animals↗
PubMed1984

Human menopausal gonadotropin/human chorionic gonadotropin-induced ovarian hyperstimulation with transient hyperprolactinemia: steroidogenesis enhanced during bromocriptine therapy in monkeys.

To examine the role of gonadotropin-induced hyperprolactinemia on reproductive function, 17 euprolactinemic ovulatory monkeys were given extended fixed dose regimens of human menopausal gonadotropin (hMG) (12 days), followed by hCG the next day, and some animals then received bromocriptine. All animals were given hMG/hCG from day 3 (D3) until D14, with hCG on D15; those in group I (n = 12) received no further therapy, while those in group II (n = 5) received bromocriptine (0.25 mg/kg X day, im) daily from the day of hCG administration until menses. Ovarian hyperstimulation developed to various degrees in all animals. Based on serum estradiol (E2) levels, 13 were high responders (E2, greater than 1000 pg/ml), 2 were medium responders (E2, 500-1000 pg/ml), and 2 were low responders (E2, 150-500 pg/ml). In group I, transient hyperprolactinemia occurred in the luteal phases in 8 of the 12 animals compared to the follicular phase levels in the same animals (P less than 0.01). In group II, bromocriptine treatment in the luteal phase prevented hyperprolactinemia, but there was no change in the menstrual cycle or luteal phase lengths; however, significant luteal phase increases in progesterone (P less than 0.005) and E2 (P less than 0.02) secretion occurred during bromocriptine therapy. Deliberate hMG/hCG studies in euprolactinemic women seem indicated to learn whether women so treated experience estrogen-progesterone-induced hyperprolactinemia like that in monkeys and, if so, to determine its consequences on the reproductive process.

Animals↗
PubMed1984

Endocrine consequences of prolonged ovarian hyperstimulation: hyperprolactinemia, follicular atresia, and premature luteinization.

Eighteen normal ovulatory cynomolgus (Macaca fascicularis) monkeys were given an extended fixed-dose regimen of human menopausal gonadotropin (hMG), which was followed by human chorionic gonadotropin (hCG) administration. Ovarian hyperstimulation developed in responsive subjects to various degrees. Based on their serum estradiol (E2) response, 16 were arbitrarily categorized as high responders (E2 greater than 1000 pg/ml), 3 were medium responders (E2 500 to 1000 pg/ml), and 2 were low responders (E2 150 to 500 pg/ml). Interestingly, one female did not respond to exogenous gonadotropin therapy. The endocrine consequences of prolonged ovarian hyperstimulation include (1) hyperprolactinemia in the luteal phase of 50% of responsive monkeys; (2) frequent atresia of growing follicles, marked by a precipitous decline in serum E2, despite continuous hMG therapy; and (3) seven monkeys with premature serum progesterone elevations up to 1 week before hCG injection, without an overt luteinizing hormone surge. Only 1 of 18 females manifested a typical midcycle luteinizing hormone surge during hMG/hCG treatment. These findings have physiologic implications that are relevant to ovulation induction and in vitro fertilization therapy in infertile women.

Animals↗
PubMed1984

Refractoriness to gonadotropin therapy: how to distinguish ovarian failure versus pseudoovarian resistance caused by neutralizing antibodies.

Ovarian resistance to exogenously administered gonadotropins and elevated serum gonadotropins, especially follicle-stimulating hormone (FSH), are considered virtually diagnostic of ovarian failure. However, similar clinical findings can be caused by circulating antibodies to gonadotropins which can neutralize the biologic activity of exogenously administered gonadotropins and can also cause falsely high gonadotropin determinations by routine double-antibody radioimmunoassay (RIA). We have used a primate model with anti-FSH antibodies to demonstrate that an acute course of combined estrogen-progestin therapy will suppress the pituitary secretion of FSH, which is markedly elevated in ovarian failure, while the false FSH elevations caused by circulating anti-FSH antibodies are not reduced by steroid negative feedback. Thus, gonadotropin (RIA) determinations before versus during an acute course of estrogen and progesterone therapy can distinguish true ovarian failure from the presence of circulating anti-gonadotropin antibodies.

Animals↗
PubMed1983

Binding of colchicine to renal tubulin at 5 degrees C.

Previous reports in the literature state that the binding of colchicine to soluble tubulin is negligible at 0 - 4 degrees C as measured by non-equilibrium binding methods. In contrast, we have detected significant binding of colchicine to tubulin at 5 degrees C. Furthermore, for the first time equilibrium dialysis has been used to measure colchicine binding. The value of the dissociation constant was 1.8 microM at 5 degrees C, and the stoichiometry of colchicine binding at 5 degrees C equaled that at 37 degrees C. Dissociation at 5 degrees C of bound colchicine was negligible over a period of 23 h, and the estimated minimal half-time of dissociation was 150 h.

Animals↗
PubMed1983

High-performance liquid chromatographic application of the Hummel and Dreyer method for the determination of colchicine-tubulin binding parameters.

An application of the Hummel and Dreyer gel chromatography procedure modified for high-performance liquid chromatography has been used to determine the dissociation constant for the colchicine-tubulin interaction at 25 degrees C. The results obtained are compared with results of other equilibrium and non-equilibrium techniques and demonstrate that the initial interaction of colchicine with tubulin must be rapid and probably reversible. This rapid and sensitive technique, which does not require radioisotopes for measurement of the binding parameters, will be extremely useful for characterization of tubulin-ligand interactions.

Animals↗
PubMed1983

Selective inhibition of follicle-stimulating hormone by porcine follicular fluid extracts in the monkey: effects on midcycle surges and pulsatile secretion.

Nonsteroidal factor(s) in porcine follicular fluid (pFF) can selectively suppress tonic follicle-stimulating hormone (FSH) concentrations when administered in the follicular phase to monkeys. Here it is demonstrated that when administered in either the early follicular phase or in the midst of the spontaneous preovulatory estradiol (E2) surge (E2 greater than or equal to 200 pg/ml), pFF preferentially inhibits FSH or blocks the FSH surge, respectively, whereas immunoassayable and bioassayable luteinizing hormone (LH) surges persist. Delay in the timing of ovulation uniformly follows follicular phase pFF administration, and corpus luteal insufficiency is often seen. The inhibitions of FSH in circulation were achieved by a decrease in amplitude and frequency of FSH pulses. No discernible effect on LH pulsatility was observed.

Animals↗
PubMed1983

Maintenance of ovulatory menstrual cycles in chronically cannulated monkeys: a vest and mobile tether assembly.

We report maintenance of apparently normal ovulatory menstrual cycles in cynomolgus monkeys up to 3 months after their placement in a vest and mobile tether assembly, with or without chronic cannulation via a femoral to vena caval catheter. Since menstrual cyclicity and characteristic hormonal profiles of the principal ovarian steroids remained normal in these monkeys, use of the vest and mobile tether apparatus described here permits long-term study of the hypothalamic-pituitary-ovarian axis during chronic cannulation without introducing overt aberrancies as a part of the experimental model.

Animals↗
PubMed1983

Pituitary and adrenal responses to the anti-progesterone and anti-glucocorticoid steroid RU 486 in primates.

RU 486 is a synthetic steroid with anti-progesterone and anti-glucocorticoid properties. While studying its acute effects on pituitary hormone secretion in cynomolgus monkeys, we found that RU 486 inhibited PRL secretion induced by an estrogen-progesterone synergy (P less than 0.025). By contrast, plasma levels of ACTH, arginine vasopressin and cortisol increased following RU 486 administration (P less than 0.05). Plasma FSH, LH, GH and TSH were unaffected by RU 486 treatment. Our findings suggest potential diagnostic and therapeutic applications of RU 486.

Adrenal Glands↗
PubMed1983

Initiation of the primate ovarian cycle with emphasis on perimenarchial and postpartum events.

In collating the issues discussed in this review, we have summarized the initiation of the primate ovarian/menstrual cycle into two conceptual illustrations. Figure 27 depicts the progression of folliculogenesis in perimenarchial monkeys; Figure 28 compares the restoration of recruitment, selection, and maturation of the dominant follicle in postpartum monkeys, with and without an infant at breast. The following conclusions, some tentative or partial, seem warranted by the data. In perimenarchial monkeys: 1. The late pubertal cascade included progression toward greater ovarian asymmetry of estradiol secretion. 2. This asymmetry of estrogen synthesis may be indicative of recruitment and selection of the dominant follicle, even though ovulation is not yet achieved. 3. Quantitative and qualitative changes in pulsatile pituitary gonadotropin secretion accompany the onset of cyclic ovarian function. 4. The enhanced biological activity of LH, especially during the preovulatory surge induced by the instigation of estrogen positive feedback in the advanced postmenarchial interval, may be a critical development step toward normal ovulatory menstrual cycles. In postpartum monkeys: 1. Reestablishment of ovulatory cycles is a gradual process in non-nursing monkeys, with initial follicular growth supporting endometrial proliferation but failing to culminate in ovulation. Immediately thereafter, ovulatory menstrual cycles ensue. 2. After nursing and weaning, resumption of ovulation is prompt, with the first menses coming after the first luteal phase. 3. Gestation-induced refractoriness of the hypothalamic-pituitary unit to estrogen positive feedback or GnRH challenges is highly transient. 4. While nursing continues, inhibition of the H-P-O axis is absolute; but after weaning the reacquisition of its functional integrity is rapid. 5. Nursing sustains the block to estrogen positive feedback, probably emanating from a mechanism(s) distinctly unlike that imposed by the pregnancy milieu. 6. Persistence of postpartum anovulation surely illustrates inadequate tonic gonadotropin secretion, as opposed to constraints arising from an inoperative surge mode of FSH/LH release.

Animals↗
PubMed1983

Effect of a call-in prescription refill system on workload in an outpatient pharmacy.

The effect of a computer-assisted call-in prescription refill system on the workload of an outpatient pharmacy was investigated. After installation of a telephone-answering device and a dedicated telephone line in the pharmacy, patients were able to call 24 hours a day and request a prescription refill. A computer system was used to screen the patient's record for drug interactions, print a new label, and update the patient's profile. Data were collected on the number of prescriptions processed per hour and per day before (period 1) and after (period 2) the system was implemented. The workload was assessed by the number of new prescriptions, refills, call-in refills, and total prescriptions processed. The mean number of prescriptions processed per hour ranged from approximately 10 to 178 during both periods. During period 2, the pharmacists processed a mean of 172 and 161 prescriptions per hour for the first and second hours of the day, respectively; for period 1, these means were 112 and 135 prescriptions, respectively. The numbers of refill prescriptions and total prescriptions dispensed during period 2 were significantly greater than those of period 1. Overall, there was a 16.9% increase in prescription volume. The computer-assisted call-in refill system had an effect on the workload and gave pharmacy management some control over the hourly work flow.

Drug Prescriptions↗
PubMed1982

Synthesis of [32P]dolichyl phosphate, utilizing a general procedure for [32P]phosphorus oxychloride preparation.

Equilibration of the phosphorus in radioactive phosphoric acid with the phosphorus in phosphorus oxychloride occurs if these compounds are refluxed together for approximately 24 h. This observation led us to develop a method for the preparation of radioactive phosphorus oxychloride on a small scale with high specific radioactivity. The labeled phosphorus oxychloride may be utilized directly in a one-pot reaction for the preparation of labeled phosphate esters or for the synthesis of more selective phosphorylating agents such as cyanoethyl phosphate. Since the method is very simple and capable of yielding highly labeled radioactive phosphate esters on a small scale, it is applicable to a number of different problems. The preparation of 32P-labeled dolichyl phosphate is described utilizing this procedure.

Chromatography, High Pressure Liquid↗
PubMed1982

Granulosa cell pyknosis in the dominant follicle of monkeys.

One of the primary morphologic criteria used as the first sign of degeneration of an antral follicle is the presence of a pyknotic nucleus in granulosa cells lining the lumen. This study was undertaken to determine whether granulosa cells with a pyknotic nucleus are also present in the putative dominant follicle. Dominance was verified by elevations of estradiol either following luteectomy or during the later stages of the follicular phase of the menstrual cycle. Some pyknosis is normal even in the viable dominant follicle at cycle day 8 or 12. Therefore, when evaluating the morphologic status of a follicle, one should examine several areas to assure proper evaluation.

Animals↗
PubMed1982

Follicle dominance and ovarian asymmetry after luteectomy in rhesus monkeys.

Previous work demonstrated that asymmetrical ovarian activity accompanies morphological asymmetry during the ovarian cycle in rhesus and cynomolgus macaques. This study was designed to determine whether functional ovarian asymmetry could be used to detect the upcoming dominant follicle (DF) even before it was grossly visible. Revealing a latent DF in this manner would permit a better estimate of the time when dominance of the follicle selected to ovulate is attained. To accomplish this, rhesus monkeys were luteectomized at midluteal phase to synchronize subsequent follicle growth, and 4 or 8 days later either the ipsilateral or contralateral ovary was removed. Unilateral ablation at day 4 (when no DF is grossly apparent) of either ovary produced symmetrical responses: the interval from luteectomy (CLX) to the next luteinizing hormone (LH) surge was extended by about 4 days in both groups (P less than 0.01), i.e., from about 12.5 days to 16.7 +/- 1.6 and 17.0 +/- 1.5 days (mean +/- SE). In contrast, hemiovariectomy at day 8 produced markedly divergent asymmetrical responses. Removal of the ipsilateral ovary 8 days after CLX did not affect the timing of the next LH surge (13.2 +/- 0.6 days), which ordinarily occurs about 12.5 days after CLX alone. However, ablation of the contralateral ovary (bearing the next DF) on day 8 extended the interval from CLX to the next LH surge from about 12.5 to 26.6 +/- 1.3 days. These findings indicate that, during the normal ovarian cycle when menses occurs 2--4 days after luteolysis, the follicle destined to ovulate becomes dominant between the 2nd and 6th day and that attainment of dominance signals the completion of a follicle selection process that begins or resumes promptly after luteolysis.

Animals↗
PubMed1982

The late pubertal cascade in perimenarchial monkeys: onset of asymmetrical ovarian estradiol secretion and bioassayable luteinizing hormone release.

Changes in ovarian function and pituitary gonadotropin secretion were studied in perimenarchial rhesus monkeys. Even in the premenarchial interval, a modest degree of asymmetrical ovarian estradiol secretion was evident. A progression toward marked asymmetry of ovarian function continued after menarche, culminating in ovulatory menstrual cycles with intermenstrual intervals of approximately 28 days. Among postmenarchial monkeys manifesting five or fewer episodes of overt uterine bleeding, no ovulations were detected despite estradiol elevations similar to those of adults in the midfollicular phase. Soon thereafter, among individuals usually having more than 10 menses, the first ovulations were likely to be achieved. The initiation of estrogen-positive feedback, driving the surge modes of gonadotropin secretion, was accompanied by the onset of a striking disparity between bioassayable vs. immunoassayable LH in the circulation. In this report we describe a cascade of late pubertal events including: 1) the gradual establishment of cyclic asymmetrical ovarian estrogen secretion in the perimenarchial interval, 2) increased pituitary responsiveness to GnRH, 3) quantitative and qualitative changes in the pulsatile secretion of pituitary gonadotropins, and 4) an enhancement of bioassayable LH secretion, especially during the preovulatory surge.

Animals↗