Gallstones in an ovarian dermoid cyst.
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Cholecystectomy↗
Biomedical subjects
A Hurwitz
Publications and source records attributed to A Hurwitz.
Hypotension during dobutamine stress echocardiography: initial description and clinical relevance.
Hypotension during exercise treadmill testing is correlated with the presence of coronary artery disease, its severity, and prognosis. The importance of hypotension during dobutamine stress testing has not been previously reported to our knowledge. We reviewed 43 cases of hypotension occurring in 42 patients out of a total of 116 consecutive stress dobutamine echocardiographic procedures performed in a total of 112 patients. Of the 42 patients with hypotension, 20 underwent cardiac catheterization. Regional wall motion abnormalities induced by dobutamine infusion were found in 13 of these patients, all of whom had significant (greater than or equal to 70% diameter reduction) coronary artery disease. The remaining seven patients without regional wall motion abnormalities did not have significant coronary artery disease at catheterization. Of the remaining 22 patients with dobutamine-induced hypotension, 20 had no induced regional wall motion abnormalities, were not catheterized, and were followed clinically. None of these patients had a cardiac event during a mean follow-up period of 11.5 months. We conclude that hypotension during dobutamine stress echocardiography in the absence of regional wall motion abnormalities does not indicate significant coronary artery disease or portend an adverse prognosis.
Aged↗
Ovarian follicular atresia as an apoptotic process: a paradigm for programmed cell death in endocrine tissues.
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Cell Death↗
Human intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding IL-1, its receptor, and its receptor antagonist.
To delineate the scope of the human intraovarian IL-1 system we used a solution hybridization/RNase protection assay to test for expression of the genes encoding IL-1, its type I receptor (IL-1R), and its receptor antagonist (IL-1RA). IL-1 transcripts were not detected in whole ovarian material from days 4 or 12 of an unstimulated menstrual cycle but transcripts (IL-1 beta much greater than IL-11 alpha) were detected in preovulatory follicular aspirates from gonadotropin-stimulated cycles. Concurrently obtained peripheral monocytes did not contain IL-1 beta transcripts but macrophage-depleted follicular aspirates did, thus implicating the granulosa cells as the site of IL-1 expression. IL-1R transcripts were detected in RNA from whole ovaries and follicular aspirates but not in RNA from peripheral monocytes. IL-1RA transcripts were detected in whole ovarian material as well as in macrophage-free follicular aspirates. Cultured human granulosa and theca cells did not contain mRNA for IL-1 beta or IL-1RA but did contain mRNA for IL-1R. Treatment of cell cultures with forskolin (25 microM) induced IL-1 beta transcripts in granulosa but not theca cells. Forskolin also increased the basal levels of IL-1R transcripts in both granulosa and theca cells but did not induce IL-RA transcripts in either cell type. Taken together, these findings reveal the existence of a complete, highly compartmentalized, hormonally dependent intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist.
Adult↗
Granulosa cell-derived insulin-like growth factor (IGF) binding proteins are inhibitory to IGF-I hormonal action. Evidence derived from the use of a truncated IGF-I analogue.
An increasing body of information now suggests that insulin-like growth factor (IGF) binding proteins (BPs) may serve as antigonadotropins at the level of the ovary. It is the objective of the present communication to evaluate the functional role of endogenous (granulosa cell-derived) IGFBPs by exploiting the unique properties of des(1-3)IGF-I, a naturally occurring IGF-I analogue characterized as a weak ligand of IGFBPs but not of type I IGF receptors. Given IGFBP-replete circumstances, des(1-3)IGF-I proved more potent (10-fold) than its intact counterpart in promoting the follicle stimulating hormone (FSH)-stimulated accumulation of progesterone by cultured rat granulosa cells. In contrast, des(1-3)IGF-I proved virtually equipotent to the unmodified principle under IGFBP-deplete circumstances. Taken together, these findings are in keeping with the notion and that the apparently enhanced potency of des(1-3)IGF-I (under IGFBP-replete conditions) is due to its diminished affinity for endogenously generated IGFBPs and that rat granulosa cell-derived IGFBPs are inhibitory to IGF (and thus inevitably to gonadotropin) hormonal action. Accordingly, the reported ability of gonadotropins to attenuate IGFBP release by granulosa cells may be designed to enhance the bioavailability of endogenously generated IGFs in the best interest of ovarian steroidogenesis.
Animals↗
Interleukin-1 stimulates ovarian prostaglandin biosynthesis: evidence for heterologous contact-independent cell-cell interaction.
An increasing body of information now suggests the existence of a complete intraovarian IL-1 system replete with ligands, receptor, and receptor antagonist. Since IL-1 is an established mediator of inflammation and since ovulation may constitute an inflammatory-like reaction, consideration may be given to the possibility that IL-1 may play an intermediary role in the ovulatory process. To further assess the above hypothesis, we have set out to determine whether IL-1 is capable of promoting ovarian prostaglandin biosynthesis, an established component of the ovulatory cascade. Cultured whole ovarian dispersates from immature (25 day old) rats constitutively elaborated major prostaglandin species (PGE2 greater than PGF2 alpha) in a cell density-dependent fashion. Treatment with IL-1 produced dose-dependent increments in prostaglandin (PGE2 greater than PGF2 alpha) accumulation as compared with untreated controls. Comparable cellular densities of untreated or IL-1 beta-treated whole ovarian dispersates elaborated substantially more PGE2 as compared with isolated granulosa or theca-interstitial cell preparations suggesting a requirement for cell-cell interaction. Indeed, cell contact-dependent reconstitution experiments involving isolated granulosa and theca-interstitial cells at a projected physiologic ratio of 4:1 revealed synergistic interactions in the elaboration of PGE2 under both basal and IL-1 beta-treated circumstances. Identical results were obtained for cell contact-independent heterologous (but not homologous) coculture experiments. Taken together, our present findings reveal optimal basal and IL-1-stimulated ovarian prostaglandin (PGE2 greater than PGF2 alpha) biosynthesis to require heterologous, contact-independent, presumably humorally-mediated, cell-cell interaction. These observations along with the demonstration of the gonadotropin-dependent preovulatory induction of ovarian IL-1 beta gene expression provide strong support for the view that IL-1 may be the centerpiece of an intraovarian regulatory loop concerned with the promotion of the preovulatory cascade.
Animals↗
Interleukin-1 is both morphogenic and cytotoxic to cultured rat ovarian cells: obligatory role for heterologous, contact-independent cell-cell interaction.
An increasing body of information now suggests that intraovarian interleukin-1 (IL-1) may play an intermediary role in the ovulatory process. Given that follicular rupture inevitably requires marked tissue remodeling and possibly cell death, we set out to examine the morphogenic potential of IL-1 under in vitro circumstances. Treatment of freshly plated whole ovarian dispersates from immature rats with any one of several batches of IL-1 (10 ng/ml) for up to 96 h produced marked time-dependent morphological alterations, including cellular retraction, rounding, clumping, aggregation, blebbing, swelling, and, ultimately, irreversible detachment. Evidence of (asynchronous) cell death consisted of reduced total cell number, diminished cellular protein content, enhanced cellular release of lactic dehydrogenase, failure to exclude trypan blue, and attenuated reduction of the tetrazolium dye 3-[4,5-dimethylthiazol-2-y]2,5-diphenyltetrazolium bromide to spectrophotometrically detectable formazan. Comparable results were obtained when using established day 4 cultures, arguing against a possible critical action of IL-1 at the time of plating. Dose-response curves revealed IL-1 beta (EC50, 0.2-0.4 ng/ml) to be substantially more potent than IL-1 alpha (EC50, 2.7-2.8 ng/ml). Importantly, the concurrent provision of an IL-1 beta-directed polyclonal antibody yielded complete immunoneutralization of the IL-1 beta effect, arguing against the possible involvement of a non-IL-1 contaminant. An unrelated polyclonal antiserum raised against insulin-like growth factor-I was without effect. IL-1 action proved relatively specific, in that tumor necrosis factor-alpha (10 ng/ml), a putative cytotoxic principle, as well as IL-1-inducible ILs (IL-2 and -6; 100 U/ml) were without effect. Although minimally effective at the level of the isolated granulosa or theca-interstitial cell, IL-1 proved highly potent in heterologous (but not homologous), contact-dependent and independent cocultures of these somatic cell types, strongly suggesting obligatory cell-cell cooperation. These observations further indicate that IL-1 action is indirect and may require the induction of an intermediary soluble principle to serve as the final effector. Taken together, these findings indicate that relatively low concentrations of IL-1 (beta >> alpha), possible of somatic ovarian cell or resident ovarian macrophage origin, are capable of exerting specific dose- and time-dependent (immunoneutralizable) morphogenic as well as cytotoxic effects at the level of ovarian cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Expression of the genes encoding the insulin-like growth factors and their receptors in the human ovary.
Insulin-like growth factor-I (IGF-I) and IGF-II have been proposed as potential regulators of ovarian function. To gain further insight as to the possible role(s) of the IGFs in human ovarian physiology, we have characterized the expression of the genes encoding the IGFs and their corresponding receptors in the human ovary using solution hybridization/RNase protection assays. IGF-I gene expression was evident in liver, placenta, and whole premenopausal ovary, but not in luteinized granulosa cells. Use of 3'- and 5'-specific antisense RNA probes revealed the presence of IGF-I mRNAs encoding both the Ea and Eb forms of the E-peptide as well as potential 5'-untranslated region splicing variants in liver, placenta, and whole menopausal ovary. Immunohistochemical studies localized the IGF-I peptide to the thecal-interstitial compartment. IGF-II mRNA transcribed from the fetal or fetal-neonatal IGF-II promoter was found in whole premenopausal ovary, luteinized granulosa cells, and placenta. Insulin and type I and type II IGF receptor mRNAs were detected in all tissues examined. Two protected probe fragments were seen with the type I IGF receptor probe in each case, suggesting the possibility of alternate splicing. These studies provide further evidence for a role of these growth factors in human ovarian function.
DNA↗
Cytokine-mediated regulation of ovarian function. Tumor necrosis factor alpha inhibits gonadotropin-supported ovarian androgen biosynthesis.
Resident ovarian macrophages have been implicated in the regulation of ovarian function, presumably through local paracrine secretion of regulatory molecules (i.e. cytokines). One such macrophage product, tumor necrosis factor (TNF) alpha, has been shown to attenuate the gonadotropin-dependent differentiation of the somatic ovarian (estrogen-producing) granulosa cell. This study examines the possibility that TNF alpha may also regulate the adjacent androgen-producing theca interstitial cell. The basal accumulation of androsterone (the major androgenic steroid), synthesized by whole ovarian dispersates from immature rats, remained unchanged following treatment with TNF alpha (30 ng/ml) alone. In contrast, concurrent treatment with increasing concentrations of TNF alpha (0.03-30 ng/ml), yielded dose-dependent inhibition of the human chorionic gonadotropin (1 ng/ml)-stimulated accumulation of androsterone. This reversible and immunoneutralizable effect of TNF alpha was characterized by a minimal effective dose of 0.1 ng/ml, a median inhibitory dose of 0.9 ng/ml, a maximal inhibitory effect of 90%, and a minimal time requirement of less than or equal to 48 h. Comparable results were obtained when using highly purified theca interstitial cells, thereby indicating that TNF alpha is capable of exerting a direct inhibitory effect at the level of the ovarian androgen-producing cell. TNF alpha action was not accounted for by alterations in the plated viable cell mass. Instead, treatment with TNF alpha resulted in significant inhibition of the human chorionic gonadotropin-supported accumulation of cAMP, the putative second messenger of gonadotropin hormonal action. TNF alpha action at sites distal to cAMP generation was associated with profound inhibition of the conversion of the [3H]pregnanolone (3 alpha-hydroxy,5 alpha-pregnane-20-one) and [3H]17 alpha-hydroxypregnanolone (3 alpha, 17 alpha-dihydroxy,5 alpha-pregnane-20-one) substrates to androsterone, suggesting stimulation of 20 alpha-hydroxysteroid dehydrogenase activity, inhibition of 17 alpha-hydroxylase/17:20 lyase activity, or both. Taken together, these findings indicate that TNF alpha, acting at relatively low concentrations, is capable of inhibiting gonadotropin-supported ovarian androgen biosynthesis by selectively modulating the activity of relevant key steroidogenic enzymes. As such, these observations suggest that the theca interstitial cell is a site of TNF alpha reception and action and that TNF alpha, possibly of resident ovarian macrophage origin, may partake in the regulation of ovarian androgen production, an effect due in part to inhibition of the activity of the key steroidogenic enzymes 17 alpha-hydroxylase/17:20 lyase.
Androsterone↗
Omeprazole and the induction of human cytochrome P-450: a response to concerns about potential adverse effects.
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Acetaminophen↗
Mexiletine effects on theophylline disposition.
The effect of mexiletine administration on steady-state plasma theophylline concentrations was studied in eight normal healthy men in a prospective open label nonrandomized two-way crossover trial. Repeated doses of 300 mg of sustained-release theophylline were given every 12 hours for 9 days. Mexiletine hydrochloride, 200 mg every 8 hours, was given for five consecutive doses starting on the morning of day 6. Mexiletine increased theophylline levels in all subjects. Mean predose (trough) levels rose from 8.1 +/- 0.1 microgram.ml-1 to 13.4 +/- 0.6 micrograms.ml-1 and AUC(0-12) from 96.8 +/- 9.1 to 160.2 +/- 3.7 micrograms.ml-1.hr. Plasma clearance was reduced by mexiletine from 44.7 +/- 5.1 to 25.4 +/- 1.2 ml.hr-1. Both N-demethylated metabolites of theophylline were decreased by 60% by mexiletine, whose levels remained within its therapeutic range. Theophylline levels returned to pre-mexiletine values when this drug was discontinued. Mexiletine reduces theophylline clearance and increases its plasma concentration by inhibiting N-demethylation of theophylline. Plasma theophylline levels should be monitored when mexiletine is added.
Adult↗
Insulin-like growth factors: the ovarian connection.
A large body of information now supports the existence of a complete intraovarian insulin-like growth factor (IGF) system replete with ligands, receptors, and binding proteins. Although much remains to be learned, the emerging consensus would suggest that the intraovarian IGF system is concerned largely with the amplification of gonadotrophin hormonal action for the facilitation of follicular growth and development. Future studies are likely to address the central issue of indispensability and the documentation of a meaningful in vivo role for this and related putative intraovarian regulators.
Animals↗
Insulin-like growth factor I as an intraovarian regulator: basic and clinical implications.
Although much remains to be learned with respect to the possible relevance of IGF-I to ovarian physiology, it may be possible at this time to tentatively formulate possible functions of IGF-I in this connection: 1. Amplification of gonadotropin hormonal action--a key requirement given the exponential nature of follicular development. 2. Integration of follicular development--an essential facet concerned with the coordination of granulosa-theca cooperation. 3. Selection of dominant follicle(s)--a speculative proposition assuming timely and selective activation of the IGF-I system in "chosen" follicles. Aside from its possible role(s) in the course of established follicular cycles, IGF-I (and/or IGF-II) may also participate in the very formation of the follicular apparatus during the late fetal/early neonatal period. Although the ovary is gonadotropin-independent at that time, we previously showed that IGF-I may well interact with VIPergic input now implicated in the morphodifferentiation of the follicular apparatus. Similarly, IGF-I may be concerned with the promotion of juvenile and early pubertal follicular gonadotropin (FSH) levels; ovarian IGF-I may have a bearing on the puberty-promoting effect of growth hormone. Indeed, an association appears to exist between isolated growth hormone deficiency and delayed puberty in both rodents and human subjects, a process reversed by systemic growth hormone replacement therapy. Given that ovarian IGF-I and its receptor may be growth hormone-dependent, it is tempting to speculate that the ability of growth hormone to accelerate pubertal maturation may be due, at least in part, to the promotion of ovarian IGF-I production and reception with the consequent local potentiation of gonadotropin action.
Animals↗
Aspartame and sucrose produce a similar increase in the plasma phenylalanine to large neutral amino acid ratio in healthy subjects.
Aspartame (L-aspartyl-L-phenylalanine methyl ester) consumption has been postulated to increase brain phenylalanine levels by increasing the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids (Phe/LNAA). Dietary manipulations with carbohydrate or protein can also produce changes in the Phe/LNAA value. To compare the effects of aspartame and carbohydrate on Phe/LNAA, beverages sweetened with aspartame, sucrose, and aspartame plus sucrose, and unsweetened beverage were ingested by 8 healthy, fasted subjects in a randomized, four-way crossover design. The beverages were sweetened with an amount of aspartame (500 mg) and/or sucrose (100 g) approximately equivalent to that used to sweeten 1 liter of soft drink. The baseline-corrected plasma Phe/LNAA values did not differ significantly following ingestion of aspartame or sucrose. Following aspartame alone, the high mean ratio increased 26% over baseline 1 h after ingestion. Following sucrose alone, the high mean ratio increased 19% at 2.5 h. Sucrose increased the Phe/LNAA value due to an insulin-mediated decrease in the plasma LNAA, while aspartame increased the ratio by increasing the plasma Phe concentration. These findings indicate that similar increases in plasma Phe/LNAA occur when healthy, fasting subjects ingest amounts of equivalent sweetness of sucrose or aspartame.
Adult↗
Ovarian granulosa cell-derived insulin-like growth factor binding proteins: modulatory role of follicle-stimulating hormone.
Recent observations disclosed the multiplicity of granulosa cell-derived high affinity insulin-like growth factor binding proteins (IGFBPs) and revealed the striking ability of high doses of FSH to suppress their constitutive release under both in vitro and in vivo circumstances. It is the objective of this communication to characterize in greater detail the modulatory effect(s) exerted by FSH on the elaboration of IGFBPs by granulosa cells from immature, estrogen-primed rats. The ability of FSH to regulate the elaboration of granulosa cell-derived IGFBPs proved dose-dependent but biphasic in nature. Specifically, FSH concentrations in the range of 1-3 ng/ml applied for 72 h produced a significant (P less than 0.05) increase in polyethylene glycol-precipitable [125I]IGF-I binding activity corresponding to all IGFBP species detectable by ligand blotting. In contrast, treatment with higher concentrations (greater than or equal to 10 ng/ml) of FSH resulted in progressive dose-dependent inhibition of the constitutive release of IGF-I binding activity (80% inhibition at the 100 ng/ml dose level) and the virtual elimination of all detectable IGFBP species. Time-course studies disclosed a significant (P less than 0.05) initial (apparent at the 24-h time point) stimulatory effect of a high dose of FSH (100 ng/ml) corresponding mostly (but not solely) to the single minor (23K) IGFBP band. In contrast, more prolonged exposure to FSH (greater than or equal to 48 h) produced progressive time-dependent decrements in IGF-I binding activity, an effect associated with a decrease in the relative representation of the major band doublet (28-29K), the 23K species being all but eliminated under these experimental circumstances. Hypophysectomy produced significant (P less than 0.05) inhibition of the subsequent in vitro release of granulosa cell-derived precipitable IGF-I binding activity strongly suggesting that (presumptively stimulatory) pituitary principles other than FSH are likely involved in the regulation of granulosa cell IGFBP release and that the trophic influence of these putative agents appears to outweight the potential disinhibition of FSH hormonal action. Taken together, these findings indicate that the pituitary regulation of granulosa cell-derived IGFBPs is complex and is not FSH-exclusive. Our findings further indicate that the ability of FSH to regulate granulosa cell-derived IGFBPs is dose- and time-dependent but biphasic in nature, an effect characterized by an early low-dose stimulatory effect and a late high-dose inhibitory effect.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Cytokine-mediated regulation of ovarian function: interleukin-1 inhibits gonadotropin-induced androgen biosynthesis.
Resident ovarian macrophages have long been recognized as potential in situ regulators of ovarian function, presumably through local paracrine secretion of regulatory molecules (i.e. cytokines). One such macrophage product, interleukin-1 (IL-1) has recently been shown to exert profound regulatory effects at the level of the ovarian granulosa cell. In this report, we examine the possibility that the adjacent theca-interstitial (androgen-producing) cell may also be a site of IL-1 reception and action. The basal accumulation of androsterone, the major androgenic steroid synthesized by whole ovarian dispersates from immature rats, in the presence of insulin (1 microgram/ml), increased 8- to 9-fold after treatment with human CG (1 ng/ml). Although IL-1 alpha or IL-1 beta (10 ng/ml) by themselves were without effect on basal androsterone accumulation, both cytokines (IL-1 beta greater than IL-1 alpha) inhibited human CG hormonal action (in the presence of insulin) in a dose-dependent manner, the maximal inhibitory effect being 75%. Similar results were obtained when using highly purified theca-interstitial cells derived from the same animal model suggesting that IL-1-attenuated androgen biosynthesis is due, at least in part, to IL-1 acting directly at the level of the theca-interstitial cells. The IL-1 effect proved relatively specific since all other known interleukins (IL-1, IL-3, IL-4, IL-5, and IL-6) were without effect. Moreover, IL-1 beta action was effectively immunoneutralized when concurrently applied with anti-IL-1 beta (but not nonimmune) sera. Significantly, the antigonadotropic action of IL-1 could not be accounted for by a decrease in the viable cell mass. Tracer studies with radiolabeled steroid substrates suggested that IL-1-attenuated ovarian androsterone accumulation is due, if only in part, to inhibition of transformations catalyzed by (theca-interstitial) 17 alpha-hydroxylase/17:20 lyase, stimulation of theca-interstitial (or granulosa 20 alpha-hydroxysteroid dehydrogenase-mediated conversions, or both. Taken together, these findings indicate that relatively low concentrations of IL-1, possibly originating from somatic ovarian cells or resident ovarian macrophages, are capable of exerting an inhibitory effect upon gonadotropin-supported androgen production. As such, these and previous observations suggest that intraovarian IL-1 may play a dual regulatory role in the developing ovarian follicle by targeting both the granulosa and theca-interstitial cells as its sites of action.
Androsterone↗
The ovarian expression of the antigonadotropic insulin-like growth factor binding protein-2 is theca-interstitial cell-selective: evidence for hormonal regulation.
To begin the process of identification and charactization of rat ovarian insulin-like growth factor binding proteins, we have undertaken to explore the ovarian expression, cellular localization, and hormonal regulation of the insulin-like growth factor binding protein-2 (IGFBP-2) gene for which an antigonadotropic potential has recently been demonstrated. To this end, a solution hybridization/RNase protection assay was employed wherein total ovarian RNA (20 micrograms) from immature (21-23 days old) female rats was hybridized with a [32P]-labeled IGFBP-2 riboprobe. As in liver, a single protected fragment (550 bases long) corresponding to IGFBP-2 transcripts was identified in whole ovarian material. Cellular localization studies revealed the IGFBP-2 gene to be exclusively expressed in the theca-interstitial rather than the granulosa cell compartment. To confirm the cellular distribution of the IGFBP-2 protein, media conditioned by cultured granulosa or theca-interstitial cells were subjected to immunoprecipitation using two IGFBP-2-directed polyclonal antisera. Expectedly, both antibodies (but not non-immune rabbit serum) readily immunoprecipitated the 28 kDa rat IGFBP-2 species generated by hepatic BRL-3A cells. Similarly, both antibodies effectively immunoprecipitated an IGFBP the size of rat IGFBP-2 elaborated by theca-interstitial cells. In contrast, neither antibody immunoprecipitated the 28-29 kDa IGFBP species elaborated by granulosa cells otherwise readily apparent in conventional Western ligand blots. Hypophysectomy resulted in a 3-fold decrease (P less than 0.05) in the relative (densitometrically-quantified) abundance of ovarian IGFBP-2 transcripts, a diametrically opposed effect (P less than 0.05) being noted at the level of the liver. In contrast, treatment of immature hypophysectomized rats with a diethylstilbestrol-containing subcutaneous silastic implant for a total of 5 days resulted in a concordant 3-fold increase (P less than 0.05) in the relative abundance of IGFBP-2 transcripts in both ovary and liver when compared with untreated hypophysectomized controls. Taken together, these findings document rat ovarian IGFPB-2 gene expression to be theca-interstitial (rather than granulosa) cell-selective, and subject to upregulatory control by pituitary principle(s) and/or by estrogens. Although equally estrogen-dependent, hepatic IGFBP-2 gene expression proved constitutive in nature and subject to (diametrically opposed) inhibitory control by (potentially distinct) pituitary principle(s).
Animals↗