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Biomedical subjects

K N Muse

Publications and source records attributed to K N Muse.

At least 19 recordsLinked to original sources
PubMed1997

Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and "add-back" therapy.

OBJECTIVE: To determine the efficacy of treating women with severe menstrual migraine headaches with GnRH agonist (GnRH-a) therapy, alone and combined with continuous estrogen-progestin "add-back." DESIGN: Nonrandomized, prospective treatment study. SETTING: Outpatient clinic in a university medical center. PATIENT(S): Five women who had repetitive, severe, migraine headaches limited to the perimenstrual period were selected carefully. INTERVENTION(S): After 2 months of basal evaluation, all subjects received GnRH-a (leuprolide acetate depot formulation, 3.75 mg IM, monthly) for 10 months. Beginning with the 5th month, "add-back" therapy (the addition of transdermal E2, 0.1 mg daily, and oral medroxyprogesterone acetate, 2.5 mg daily) was initiated. MAIN OUTCOME MEASURE(S): Patients rated headache severity from 0 (absent) to 3 (severe) each day; these were combined each month to obtain a cumulative score for that month. In addition, patients were asked their overall assessment of the treatments. RESULT(S): The mean headache scores for the GnRH-a treatment months (4.0 +/- 1.5, mean +/- SEM) and for the GnRH-a and "add-back" treatment months (3.1 +/- 0.7) were each significantly lower than those of the control months (15.3 +/- 2.4). The patients uniformly found both treatments to be well tolerated and near-curative for their condition. CONCLUSION(S): Gonadotropin-releasing hormone agonist administration, alone or with "add-back" therapy, is a very effective treatment for carefully selected patients with severe, perimenstrual migraine headaches.

Administration, Cutaneous↗
PubMed1996

Regulation of granulosa cell-derived ovarian metalloproteinase inhibitor(s) by prolactin.

Increased prolactin concentrations are known to inhibit the ovarian proteolytic enzyme cascade associated with follicular rupture. It is not known whether there is also an effect of prolactin on endogenous proteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). We sought to study the effect of prolactin on ovarian metalloproteinase inhibitors in cultured rat granulosa cells. Granulosa cells were cultured for 24 h with prolactin (0-1000 ng ml-1) in the absence or presence of LH. Metalloproteinase inhibitor activity in the conditioned culture media was measured by a colorimetric assay. Prolactin at 1000 ng ml-1 increased inhibitor activity by 2.86 +/- 0.63 times. Expression of mRNA encoding TIMP-1 measured by Northern analysis increased by 2.34 +/- 0.34 times with 100 ng prolactin ml-1 and by 2.43 +/- 0.42 times with 1000 ng prolactin ml-1 compared with control cultures (no LH, no prolactin). In the presence of LH, expression of mRNA encoding TIMP-1 and inhibitor activity increased by 2.60 +/- 0.6 and 4.60 +/- 0.54 times, respectively. However, no further change in mRNA expression or inhibitor activity was apparent with the addition of prolactin to LH-treated cultures. Prolactin had no effect on expression of mRNA encoding TIMP-3 in the absence or presence of LH, although LH stimulated a 1.7-fold increase in mRNA encoding TIMP-3 compared with controls. Addition of prolactin had no effect on media concentrations of oestradiol or progesterone. These data demonstrate that metalloproteinase inhibitor activity increases with increasing doses of prolactin; however, when LH was added, this effect was no longer seen. With an increase in metalloproteinase inhibitor activity, tissue metalloproteinase action could be decreased, providing a possible explanation for the local inhibition on pre- and peri-ovulatory pathways by hyperprolactinaemia.

Animals↗
PubMed1995

Dirithromycin increases ethinyl estradiol clearance without allowing ovulation.

OBJECTIVE: To use a novel, sensitive study design to detect a potential oral contraceptive (OC) and dirithromycin drug interaction by assessing the pharmacokinetics of the ethinyl estradiol (E2) component of a common OC and the potential failure of OC effectiveness. METHODS: In this nonblinded study, 20 healthy women using Ortho Novum 7/7/7-28 were selected for a three-OC-cycle study. Baseline measures included E2 and progesterone serum levels on days 21, 23, 25, and 27 of cycle one and days 1, 3, 5, and 7 of cycle two. During cycle two, 24-hour blood sampling and radioimmunoassay analysis for ethinyl E2 pharmacokinetics were performed on day 8 and pelvic ultrasound on day 13. Oral dirithromycin 500 mg/day for 14 days began on day 21 of cycle 2. After starting dirithromycin, cycle two and three serum E2, progesterone, and serial ethinyl E2 levels and pelvic ultrasound replicated the baseline schedule. Ovulation was assumed if E2 concentration was greater than 50 pg/mL, progesterone concentration was greater than 3 ng/mL, or if an ovarian cyst greater than 10 mm was present on ultrasound. RESULTS: Pharmacokinetic analysis demonstrated a small (7.6%) but statistically significant decrease (P = .03) in the mean ethinyl E2 24-hour area under the curve and an increase in apparent oral clearance. No woman ovulated, based on E2 levels and progesterone concentrations or ultrasound. CONCLUSION: Dirithromycin increased the apparent oral clearance of ethinyl E2. The clinical importance of the interaction may be negligible because no woman ovulated or had compromised OC effectiveness in this small series.

Adolescent↗
PubMed1994

Antiprogesterone (RU486) effects on metalloproteinase inhibitor activity in human and rat granulosa cells.

OBJECTIVE: To determine if granulosa cells are a source of metalloproteinase inhibitor activity and whether P regulates this activity. DESIGN: Inhibitor activity was measured in media from human and rat granulosa cells cultured with the antiprogesterone mifepristone (RU486). Human granulosa cells were obtained at the time of oocyte retrieval from gonadotropin-stimulated patients after hCG administration. Rat cells were collected from gonadotropin-primed animals before the LH surge. Human and rat cells were cultured for 24 hours in the absence or presence of LH (100 ng/mL or 3.3 nmol/L) and/or RU486 (5 microM or 50 microM). Inhibitor activity and P were measured in the media. SETTING: Reproductive Endocrinology Laboratories, University of Kentucky. RESULTS: Media from human granulosa cells contained metalloproteinase inhibitor activity and the addition of LH did not change this activity. RU486 at 50 microM decreased inhibitor activity in cells cultured in the absence or presence of LH (0.59 +/- 0.12- and 0.24 +/- 0.18-fold change, respectively, versus control cultures; mean +/- SEM). In rat granulosa cells, inhibitor activity increased with LH treatment (1.97 +/- 0.12-fold change). RU486 decreased the activity present in cells cultured in the presence of LH. Progesterone production was stimulated by LH in both human and rat granulosa cells (3.71 +/- 0.90- and 7.18 +/- 0.24-fold change, respectively). In the human cells, RU486 inhibited P production whereas RU486 stimulated P production in the rat cells. CONCLUSIONS: These findings demonstrate for the first time that human granulosa cells are a source of metalloproteinase inhibitor activity. The decrease in granulosa cell-derived inhibitor activity by RU486 suggests that P stimulates inhibitor activity. Thus, P may regulate proteolysis associated with follicular rupture via its ability to stimulate granulosa cell production of metalloproteinase inhibitors. Differences in P production between the human and rat cells may be due to differences in hormonal stimulation regimens (i.e., hCG exposure).

Animals↗
PubMed1994

Galanin: a novel intraovarian regulatory peptide.

Galanin is a 29-amino acid peptide that acts as a neuropeptide in many tissues. To date, galanin action and the hormonal regulation of galanin gene expression have not been described in the ovary of any species. To study possible ovarian expression and regulation of galanin, immature gonadotropin-primed rats were given hCG (10 IU), and their ovaries were collected 0, 4, 8, 12, and 20 h after hCG treatment for determination of galanin messenger RNA (mRNA) concentration by solution hybridization. Galanin mRNA levels progressively increased after hCG administration, peaking at 12 h (2.4-fold increase vs. 0 h), with a subsequent return to 0 h levels at 20 h. To determine a possible ovarian role for galanin, rats were killed 48 h after gonadotropin administration, their ovaries were removed, and granulosa cells were harvested. These cells and the ovarian tissue remaining after granulosa cell collection (i.e. "shells") were each cultured for 24 h with increasing concentrations of galanin (0, 10, 100, and 1000 nM) in the presence or absence of LH. The medium was examined for steroid production and metalloproteinase inhibitor activity. In granulosa cell cultures, galanin increased the levels of estradiol by 26% and had no effect on progesterone, but decreased metalloproteinase inhibitor activity by 61% in the conditioned medium. In the shell cultures, galanin increased estradiol, progesterone, and androstenedione in the medium, suggesting that galanin acts on cells other than granulosa cells or that galanin action requires a paracrine interaction between granulosa and thecal cells. Our data demonstrate that galanin message is increased by hCG, and that galanin acts to amplify ovarian steroidogenesis while decreasing metalloproteinase inhibitor activity. These findings establish that ovarian galanin mRNA is hormonally stimulated and that galanin acts as an intraovarian regulatory peptide.

Animals↗
PubMed1994

Detection of a unique 32-kd protein in the peritoneal fluid of women with endometriosis.

OBJECTIVE: To test the hypothesis that endometriotic tissue secretes endometriotic-specific proteins into the peritoneal fluid (PF) of women with endometriosis. DESIGN: A prospective design was utilized in this study. SETTING: Tertiary care, university-based center and reproductive endocrinology laboratory. PARTICIPANTS: Women of reproductive age who were infertile with endometriosis (n = 19), as well as without endometriosis (n = 7), and fertile women undergoing tubal ligation (n = 6). INTERVENTIONS: Collection of PF fluid via laparoscopy. MAIN OUTCOME MEASURES: Peritoneal fluid proteins were isolated and assessed by two-dimensional polyacrylamide gel electrophoresis. RESULTS: Two-dimensional electrophoresis of PF proteins isolated a group of proteins (M(r) = 32 to 40 kd, pI = 4.5 to 5.2) in all PF samples that was similar to the rat endometriotic implant-specific protein, Endo-1. This group of proteins consisted of 5 to 12 individual proteins with endometriosis PF containing a significantly higher number of proteins (median = 11) compared with either PF from infertile women without endometriosis (median = 8) or from women undergoing tubal ligation (median = 7). In addition, one protein (M(r) = 32 kd, pI = 5.8), termed EPF-32, was detected predominantly (18 of 19 samples analyzed) in PF from women with endometriosis. This protein was also detected in PF from infertile women without endometriosis (2 of 7 samples) but not in the PF of fertile women undergoing tubal ligation (0 of 6 samples). The appearance of this protein was not associated with the severity of endometriosis. CONCLUSION: It is concluded from this study that PF from women with endometriosis predominantly contains a 32-kd protein (EPF-32) compared with the PF of women without the disease. The role of EPF-32 in the pathophysiology of endometriosis is not established but this protein may function as a diagnostic marker for endometriosis.

Ascitic Fluid↗
PubMed1993

The presence of luteinized unruptured follicle syndrome and altered folliculogenesis in rats with surgically induced endometriosis.

OBJECTIVE: Our purpose was to determine in the rat model whether endometriosis could influence ovarian function by altering oocyte release or folliculogenesis. STUDY DESIGN: We histologically examined the ovaries of reproductively cycling rats with (n = 16) and without (n = 10) surgically induced endometriosis. The rats in these two groups were further subdivided into unilaterally ovariectomized or ovarian-intact groups. Serial sections of ovaries were examined, and follicular development and frequency of luteinized unruptured follicles were determined. RESULTS: A significant tenfold increase in the number of luteinized unruptured follicles was observed in the ovaries from rats with endometriosis (2.7 per rat) compared with unoperated and sham-operated control groups (overall mean 0.26 per rat, p < 0.05). Additionally, ovaries from unilateral ovariectomized animals with endometriosis contained four times as many luteinized unruptured follicles (four per rat) as did the ovaries from bilaterally ovarian-intact rats with endometriosis (1.40 per rat, p < 0.01). Fewer follicles were present in rats with endometriosis (180 follicles per ovary) than in control rats (231 follicles per ovary, p < 0.05). CONCLUSION: In the rat model the presence of ectopic endometrium is associated with an increased frequency of luteinized unruptured follicles and altered follicular development.

Animals↗
PubMed1991

Spontaneous and steroid-induced recurrence of endometriosis after suppression by a gonadotropin-releasing hormone antagonist in the rat.

Recurrent endometriosis in women is difficult to study because of the ethical consideration of performing repeated surgeries. Previously in the rat model we described therapeutic regression of endometriosis with the gonadotropin-releasing hormone antagonist antide. Presently we report the spontaneous and steroid-induced recurrence of endometriosis after withdrawal from antide therapy. Rats with endometriosis received antide or vehicle on days 0 (proestrus), 3, 6, and 9 and were killed on days 0, 6, 12, 18, 24, 30, and 42 (n = 4 antide-treated and 4 vehicle-treated rats killed per day). Additional antide-treated rats (n = 4 per treatment) received estrogen, progesterone, both estrogen and progesterone, cholesterol, and no steroid on day 9 and were killed on day 12. Antide significantly suppressed endometriotic implant size on days 12, 18, and 24. However, implant size spontaneously returned to pretreatment values by day 30. Administration of steroids on day 9 elicited regrowth of antide-suppressed endometriosis (estrogen plus progesterone greater than estrogen, progesterone, or cholesterol greater than no steroid) by day 12. This resilience of endometriosis offers an explanation for treatment failure and recurrence of the disease in women.

Animals↗
PubMed1991

Intrabursal administration of protein kinase or proteinase inhibitors: effects on ovulation in the rat.

OBJECTIVE: To test the hypothesis that inhibition of protein kinase (PK) activity or proteolysis inhibits ovulation. DESIGN: Rats were injected intrabursally with protein kinase (H9 or staurosporin) or proteinase (alpha 2-macroglobulin) inhibitors and oocyte release was evaluated. SETTING: Clinical Research Laboratory, Center for Reproductive Medicine, University of Kentucky Medical Center. PARTICIPANTS: Immature rats stimulated with pregnant mare serum gonadotropin. INTERVENTIONS: Staurosporin (1 or 10 microM), H9 (1 mM), alpha 2-macroglobulin (835 microIU of activity); or vehicle was injected into the right ovarian bursa. The left ovarian bursa remained intact. Animals immediately received human chorionic gonadotropin (hCG). MAIN OUTCOME MEASURES: Analysis of oocyte release and ovarian morphology. RESULTS: Oocyte release from the inhibitor-treated side decreased for the H9 group (8.1 +/- 1.9 fewer oocytes released, P less than 0.001) and the 10 microM staurosporin group (5.5 +/- 0.6, P less than 0.001). No change in oocyte release was observed in the 1 microM staurosporin, alpha 2-macroglobulin, or vehicle injected groups. Histologic examination of vehicle treated ovaries demonstrated numerous developing corpora lutea (CL; 20.5 +/- 2.1 CL/ovary) and a lack of preovulatory follicles. In contrast, ovaries treated with PK inhibitors contained unruptured preovulatory follicles coincident with fewer forming CL (11.5 +/- 3.5 CL/ovary). CONCLUSIONS: Inhibition of PK activity in vivo suppresses ovulation, demonstrating that protein phosphorylation plays an important intermediary role in the ovulatory process.

Alkaloids↗
PubMed1990

Follicular atresia and infertility in rats treated with a gonadotropin-releasing hormone antagonist.

Adverse effects of the GnRH antagonist Antide on folliculogenesis and fertility were noted when we were evaluating the therapeutic value of Antide on endometriosis in a rat model. Cyclic rats with (n = 56) and without (n = 18) surgically induced endometriosis received Antide (2 mg/kg) or vehicle at noon on days 0 (proestrus), 3, 6, and 9. Rats were killed at noon on days 0, 6, 12, 18, 24, 30, 42, and 165. The number of antral follicles and the number of atretic antral follicles evaluated did not differ (P greater than 0.05) between endometriosis and control rats. Antide-treated rats had more (P less than 0.05 ) atretic antral follicles (64.7%) than vehicle-treated rats (15.3%). Antide-treated rat ovaries contained fewer corpora lutea than those of vehicle-treated rats on days 6, 12, and 18. No corpora lutea were found in Antide-treated rat ovaries after day 18. The abnormal ovarian morphology of the Antide-treated rats persisted for the duration of the project (165 days). Fertility (rats without endometriosis) was assessed by mating vehicle-and Antide-treated rats at spontaneous proestrus (n = 8) for eight posttreatment cycles as well as after follicular stimulation (n = 2). All vehicle-treated and no Antide-treated rats became pregnant. No oocytes were found in the oviducts of Antide-treated rats after eight cycles, indicating that ovulation had not occurred. The serum FSH and estradiol concentrations in the rats treated with Antide were lower (P less than 0.05) on days 6, 12, and 18, but rose to values equal to (days 24 and 30) or greater than (day 42) those in vehicle-treated rats. Serum progesterone levels in rats treated with Antide were lower (P less than 0.05) than those in vehicle-treated rats on all days tested. In conclusion, at a dosage sufficient to suppress reproductive cyclicity (and elicit the regression of endometriosis), Antide also caused long term follicular atresia and infertility.

Animals↗
PubMed1990

Cyclic pelvic pain.

Cyclic pelvic pain is a common gynecologic problem caused by relatively few diseases, which usually can be diagnosed and remedied quickly. Some complaints reflect normal physiologic aspects of the menstrual cycle (mittelschmerz, menstrual awareness). Premenstrual syndrome can be diagnosed, but an effective and convenient treatment is lacking. Dysmenorrhea is the commonest source of cyclic pain, diagnosed by its characteristic history and rapid relief on administration of antiprostaglandin agents. Endometriosis is diagnosed surgically and best treated either surgically then, or medically by danazol or GnRH agonists. In contrast, adenomyosis is a problem commonly encountered in later life, and hysterectomy is usually needed for both definitive diagnosis and treatment.

Abdominal Pain↗
PubMed1989

Plasminogen activator and plasminogen activator inhibitor in human preovulatory follicular fluid.

To evaluate the roles of plasminogen activator (PA) and PA inhibitor (PAI) in human ovulation, we obtained follicular fluid and granulosa cells from individual preovulatory follicles of patients undergoing gamete intrafallopian tube transfer. The follicular fluid samples (n = 25) were analyzed for total tissue-type PA antigen, PA enzyme activity by fibrin autography, PAI activity, PAI type 1 (PAI-1) antigen, and PAI-1 mRNA. The follicular fluid of preovulatory follicles contained low levels of total tissue-type PA antigen (less than 1 ng/mL). Fibrin autography experiments indicated little or no detectable PA activity associated with free or unbound PA. The results of the PAI activity assay and PAI-1 antigen determination support the concept of a relative abundance of PAI compared with PA. Hybridization analysis was used to measure the relative amounts of granulosa cell PAI-1 mRNA. The levels of PAI-1 mRNA correlate with follicular fluid PAI concentrations in individual follicles. Taken together, these results support the idea that there is very little free, or active, PA in follicular fluid of human preovulatory follicles, but there is an abundance of PAI. Furthermore, PAI-1 produced by the granulosa cells may represent a major form of PAI in follicular fluid.

Antigens↗
PubMed1988

Expression of plasminogen activator (PA) and a PA inhibitor in human granulosa cells from preovulatory follicles.

Studies with rat ovarian cells indicate that proteolytic enzymes, such as plasminogen activator (PA), play a role in the tissue remodeling that occurs before ovulation. In the rat, gonadotropins appear to increase granulosa cell tissue-type plasminogen activator (t-PA) content by increasing the cellular concentration of t-PA mRNA as well as by modulating the activity of a specific PA inhibitor (PAI). We obtained granulosa cells from preovulatory follicles of women undergoing either in vitro fertilization or gamete intra-fallopian tube transfer in order to evaluate the roles of PA and PAI in human ovulation. Samples of granulosa cell total RNA were hybridized with probes for t-PA, urokinase-type PA, PAI type 1 (PAI-1), or inhibin A-chain (as a control). Northern analyses revealed that the RNA of granulosa cells from preovulatory follicles contained little or no detectable PA mRNA. In contrast, two species of PAI mRNA were detected in relative abundance. The signal intensity produced by the PAI-1 probe varied by about 8-fold among patient samples, suggesting that PAI-1 may be useful as a marker of follicular maturation and differentiation. These results demonstrate that human granulosa cells collected immediately before ovulation contain PA inhibitor mRNA, yet have little or no PA mRNA.

Cells, Cultured↗
PubMed1987

Hormonal dynamics during luteal-follicular transition.

To gain insights into the neuroendocrine basis for the initiation of folliculogenesis, the hormonal dynamics during the period from the late luteal to the early follicular phase of the menstrual cycle (the luteal-follicular transition) were examined. Blood samples were obtained at 2-h intervals for 5 consecutive days in seven women and at 15-min intervals for 8 h on each of 4 consecutive days in five women. The results indicate that the luteolytic process, as reflected by an exponential decline of both serum estradiol and progesterone levels, began at least 64 h before the onset of menses. During estradiol and progesterone withdrawal, there was a selective increase in mean serum FSH levels (P less than 0.001) beginning 24 h before and reaching a peak 24 h after the onset of menses. The frequency of LH pulses increased slightly but not significantly during this period, with a significant rise in mean serum LH levels on the day of menses. Thus, an acute rise in FSH concentrations the day before and in LH concentrations the day after the onset of menses occurs during luteal-follicular transition. The dissociation of FSH and LH secretion observed suggests that additional neuroendocrine events other than changes in pulsatile GnRH secretion may be operative during this period. These findings indicate that the initiation of folliculogenesis for the ensuing cycle occurs during the late luteal phase by a process of selective augmentation in FSH secretion independent of hypothalamic GnRH secretion. This event may ultimately prove to be a manifestation of the action of recently characterized ovarian peptides on FSH secretion.

Adult↗
PubMed1986

Calcium-regulating hormones across the menstrual cycle.

Midcycle elevations of serum PTH, calcitonin (CT), and 1,25-dihydroxyvitamin D [1,25-(OH)2D] in women have been reported. To examine the effects of cyclic changes in ovarian steroid secretion on calcitropic hormone concentrations, we used a cytoreceptor assay for 1,25-(OH)2D and homologous RIAs for PTH and CT to measure these hormones in daily blood samples obtained from six women throughout the menstrual cycle. Significant changes in serum PTH, CT, 1,25-(OH)2D, calcium, and phosphorus concentrations during the cycle were not found; transverse means (+/- SE) were 101 +/- 3.5 pg/ml for PTH, 30.8 +/- 1.8 pg/ml for CT, and 40.1 +/- 1.7 pg/ml for 1,25-(OH)2D. In addition, CT reserve was assessed by calcium infusion (3 mg/kg, iv, in 10 min) during the early and late follicular and midluteal phases of the cycle. Although serum CT increased significantly (P less than 0.01) after calcium infusion, the mean (+/- SE) increment (23.2 +/- 2.2 pg/ml) did not significantly differ in the three phases of the cycle (early follicular, 23.8 +/- 4.0; late follicular, 23.3 +/- 3.4; midluteal, 22.5 +/- 4.1). Our data do not support previous reports of midcycle elevations in serum PTH, CT, and 1,25-(OH)2D concentrations, and we conclude that serum concentrations of the calcitropic hormones do not significantly vary during the menstrual cycle.

Adult↗
PubMed1984

The premenstrual syndrome. Effects of "medical ovariectomy".

In a crossover study conducted over a six-month period in eight patients with well-characterized premenstrual syndrome, physical and behavioral symptoms were relieved by daily administration of an agonist of gonadotropin-releasing hormone. The reversible "medical ovariectomy" attained with this agonist suggests that it may be an effective and rational treatment for this distressing syndrome in the short term. Whether prolonged therapy would be safe and effective, or even necessary, remains to be determined.

Adult↗