Systemic lupus erythematosus in men. Genetic and endocrine features.

Sixteen men with systemic lupus erythematosus (SLE) were examined to assess their genetic and hormonal status. The results of buccal smears in 13 patients examined were normal. Hormonal profiling was done in eight patients receiving no steroid therapy. Four patients had elevated plasma estradiol levels (30, 35, 55, and 103 pg/mL; normal, 12 to 23 pg/mL) and elevated plasma estrone levels (115, 150, 155, and 160 pg/mL; normal, 48 to 100 pg/mL). One patient had a decreased serum testosterone level (134 ng/dL; normal, 300 to 1,000 ng/dL), with an elevated luteinizing hormone (LH) level (4.2 ng/mL; normal, 1.6 to 4.0 ng/mL). One patient had an elevation in both levels of serum follicle-stimulating hormone (17.6 ng/mL; normal, 1 to 5 ng/mL) and LH (10.0 ng/mL). Two patients given infusions of 3H-androstenedione and 14C-testosterone had normal findings from kinetic studies of these hormones. Hyperestrogenemia and hypoandrogenemia observed in some men with SLE suggest that female sex hormones may create an immunologic milieu that facilitates the autoimmune phenomena.

Oxytocin release and uterine activation during parturition iin rabbits.

Plasma oxytocin was measured by a specific RIA in blood of pregnant and parturient rabbits obtained through an indwelling cardiac catheter. Uterine activity was continuously recorded by means of indwelling intrauterine balloons. Plasma oxytocin concentrations were low throughout gestation (mean +/- SE, 16.1 +/- 2.0 pg/ml), with no rise toward term. During parturition, a significant increase in plasma oxytocin was observed in all but 3 of 21 rabbits studied. Plasma oxytocin rose rapidly and reached high levels within minutes of the beginning of labor contractions. The mean concentration was 193 +/- 55 pg/ml (SE) 30--60 sec before the expulsive phase. The highest oxytocin concentrations were usually observed at the delivery of the first fetus (mean, 258 +/- 89 pg/ml); this was followed by a rapid decline. Baseline levels were reached in 20--60 min. Uterine activity during parturition was well correlated with plasma oxytocin; an abrupt increase was observed a few minutes (5.1 +/- 1.2 min) before the expulsion of the young, followed by a gradual disappearance over 30--70 min. Little or no circulating oxytocin was detected during delivery in 3 rabbits. In these, the course of parturition was abnormal and protracted, resulting in a high percentage of stillborn young. The series of strong contractions associated with normal delivery was absent. By contrast, abortion in 2 rabbits was associated with elevated plasma oxytocin levels and increased uterine activity. These findings indicate that a substantial amount of oxytocin is released into the circulation during delivery and suggest that the normal activation of the uterus at parturition depends on oxytocin. The stimulus eliciting the release of oxytocin is not known. Dilatation of the birth canal by the passage of a fetus was not consistently followed by detectable oxytocin release, and during delivery, a second release of oxytocin was often unrelated to any apparent stimulus. Intact spinal cord caudal to T5 does not appear to be essential for the release of oxytocin at parturition, since spinal transsection in 2 rabbits was associated with normal oxytocin release at delivery. Injections of synthetic oxytocin caused a dose-dependent increase in plasma oxytocin and uterine activity. Disappearance of oxytocin from the circulation followed a double exponential curve; the mean half-life of the initial rapid phase was 1.82 min after single injections and the half-life of the low component was 26.5 min. The initial volume of distribution was close to the volume of the vascular compartment, and the total apparent volume of distribution was about twice the size of the extracellular compartment. After constant infusions, a half-life of 3.6 min was obtained for the uncorrected values during the initial phase.

Release of oxytocin and prolactin by suckling in rabbits throughout lactation.

Plasma oxytocin and PRL were measured in serial samples of blood collected from lactating rabbits nursing five to seven (mean, six) young on a once-daily suckling regimen. Each suckling episode lasted 4.0 +/- 1.1 (+/- SD) min on the average. Samples were obtained by means of an indwelling cardiac catheter before and 1, 3, 5, 10, 20, 30, and 60 min after suckling began. Measurements were performed at several stages of early, mid-, and late lactation. Oxytocin levels rose to peak values during suckling and declined rapidly after suckling stopped. PRL levels, on the other hand, did not reach peak values until 1-5 min after suckling had stopped, at which time plasma PRL concentrations plateaued and, in early and midlactation, were sustained at peak levels for 2-3 h; in late lactation, PRL secretion was not sustained after suckling had ceased. Peak PRL levels were relatively constant throughout most of lactation, with no significant differences between groups until late in lactation, when peak levels fell rather abruptly from a mean of 74 +/- 33.5 to 10.5 +/- 13.3 (+/- SD) ng/ml around day 25 in spite of a constant number of young and constant suckling frequency. Suckling failed to elicit any PRL release on day 30, but the administration of fluphenazine, a dopamine antagonist, did cause a rise in plasma PRL. Oxytocin release increased with advancing lactation, rising, on the average, 40 pg/ml on day 2 and to 250 and 490 pg/ml in mid- and late lactation, respectively. Dopaminergic agonist and antagonist drugs given to the doe before the nursing episode did not influence oxytocin release in response to suckling. Without a rise in plasma oxytocin, the young obtained no milk, but above a threshold level, there was no significant correlation between peak oxytocin levels and milk yield. When suckling failed to induce PRL secretion, milk secretion ceased rapidly in spite of copious oxytocin secretion. The failure of suckling to induce PRL release in late lactation, therefore, appears to be an important factor in the cessation of lactation.

Oxytocin in the corpus luteum of the cynomolgus monkey (Macaca fascicularis).

To determine if oxytocin (OT) is present in cynomolgus monkey corpus luteum, OT was measured by a specific and sensitive RIA in 13 corpora lutea, ovarian venous plasma on the ipsilateral side and peripheral venous plasma at different stages of the luteal phase. Serial dilution of acetic acid extract of the corpus luteum showed parallelism with standard OT in the RIA. Total content of OT in corpus luteum was 1.9 +/- 0.5 ng (mean +/- SEM) with a content of 0.4-0.8 ng in early luteal phase, 1.0-6.2 ng in midluteal phase, and 0.4-0.7 ng in late luteal phase. OT concentrations in corpus luteum were 21.0-75.2 ng/g wet wt in early luteal phase, increasing to 34.4-602.5 ng/g in midluteal phase; and declining to 3.4-117.4 ng/g in late luteal phase. OT concentrations per mg protein in the corpus luteum were 0.05-19.6 ng with peak concentrations of 14.7-19.6 ng/mg protein on day 22. Sephadex G-25 column chromatography of the corpus luteum extract revealed a single peak for binding activity similar to that of synthetic OT on the RIA. Ovarian vein blood from the same side as the corpus luteum had a significantly higher OT concentrations of 161.2 +/- 29.7 pg/ml on days 15-24 than 16.8 +/- 3.6 pg/ml on days 25-28 (P less than 0.01) and peripheral plasma OT levels of 23.2 +/- 3.4 pg/ml (P less than 0.025). Our findings indicate that OT is present and probably produced by monkey corpus luteum with peak OT concentrations found in midluteal phase. Thus OT may play a role in primate corpus luteum function.

Human ovaries contain immunoreactive oxytocin.

Ovarian tissues (n = 26) obtained at surgery were assayed for oxytocin (OT) concentrations in different parts of the ovary by a specific and sensitive RIA after homogenization and extraction with 0.4 M acetic acid. Chromatography of the extract on a Sephadex G-25 column revealed a single peak identical to synthetic OT, as measured by RIA. Corpora lutea of the menstrual cycle had 10.8-53.0 ng immunoreactive OT/g tissue (n = 7), while those of early pregnancy had a concentration of 106.0 ng/g (n = 1). Ovarian stromal tissue had either undetectable or lower concentrations of OT (0-21.0 ng/g; n = 5) than the corpus luteum from the same ovary. While a luteoma of term pregnancy (n = 1), a benign cystadenoma (n = 2), and an endometriotic cyst (n = 1) had no detectable immunoreactive OT, the concentrations of immunoreactive OT were 20.0 ng/g in a thecoma, 1.4, 20.0, and 60.0 ng/g in preovulatory follicles (n = 3), and 41.0 and 37.0 ng/g in polycystic ovaries (n = 2). In one patient with premature ovarian failure, the ovaries had 9.0 ng/g and undetectable immunoreactive OT. These findings indicate the presence of immunoreactive OT in human ovaries, with significant concentrations in the corpus luteum and preovulatory follicles. It is probable that these tissues produce OTs or an OT-like material which may function as an ovarian luteolytic agent.

Baboon corpus luteum: autonomous pulsatile progesterone secretion and evidence for an intraluteal oscillator demonstrated by in vitro microretrodialysis.

Pulsatility of serum progesterone (P) is usually ascribed to stimulation of the corpus luteum (CL) by pulsatile release of pituitary LH. We investigated P secretion by the primate CL by performing microretrodialysis on 6 fresh CL obtained at laparotomy from baboons (Papio anubis) with well defined menstrual cycles. Individually microdialyzed for 24-26 h with Dulbecco's Modified Eagle's Medium and Ham's F-12 enriched with HEPES buffer in a perifusion chamber, the retrodialyzed fluid was collected every 10 min and measured for P, estradiol, and 17 alpha-hydroxyprogesterone by specific and sensitive RIAs. The chronodynamics of hormone secretion were analyzed for pulse detection by PC-Pulsar 3.0. All 6 CL (2 each from early, LH +1 to +5; mid, LH +6 to +10; and late luteal phases, LH +11 to +15) demonstrated pulsatile secretion of P in vitro, with distinct and detectable peaks over the 24-26 h studied. The CL secreted 23-27 pulses of P in 24 h in early luteal, 8-20 pulses in midluteal, and 6-19 pulses in late luteal phases. Peak lengths were 23.8 +/- 18.5 to 35.7 +/- 17.1 min. Four CL gave interpeak intervals of 46-55 min, whereas two gave intervals of 136-137 min. Analysis of distribution of pulses against different interpulse intervals in individual CL and all CL together revealed a bell-shaped distribution, with the largest number of pulses seen at an interpulse interval of 21-40 min. Because of the low concentrations of estradiol and 17 alpha-hydroxyprogesterone retrodialyzed, a similar analysis of these data was not possible. Histological examination of the tissue at the termination of the experiment using hematoxylin and eosin and localization of 3 beta-hydroxysteroid dehydrogenase activity indicates that the steroidogenic potential of the tissue is minimally affected, although some morphological changes do occur. Our findings suggest autonomous pulsatile P secretion by the primate CL, indicating local control by and the presence of an intraluteal oscillator or pulse generator for P secretion.

Oxytocin in maternal circulation and amniotic fluid during pregnancy.

Oxytocin (OT) was measured by a specific and sensitive RIA in plasma and amniotic fluid throughout pregnancy. OT was detectable in 84.5% of 362 maternal plasma samples and showed a slow and fluctuating increase towards term with a significant sharp peak at 39 weeks of gestation. There was a highly significant correlation between mean plasma OT and the week of gestation (r = 0.5419, P less than 0.005). The minute to minute variability in plasma OT during pregnancy and labor in 7 subjects showed episodic release of OT with two or three spurts per 10 min, with the amplitude of the spurts being greater during labor. Serial maternal plasma OT throughout pregnancy in 10 patients revealed good concentrations of OT (greater than 10 pg/ml) in patients who subsequently had spontaneous labor and no intrapartum uterine dysfunction. Poor (less than 10 pg/ml) or undetectable OT levels were found in patients who subsequently developed intrapartum uterine dysfunction which necessitated cesarean section. OT was detectable in 89.7% or 87 amniotic fluid samples, with a mean +/- SE of 7.8 +/- 3.6 pg/ml at 14--15 weeks, 43.9 +/- 14.7 pg/ml at 40 weeks, and 30.8 +/- 10.5 pg/ml at 41--42 weeks. The significance of these findings is discussed in relation to the role and origin of OT in pregnancy and parturition.

Oxytocin levels and disappearance rate and plasma follicle-stimulating hormone and luteinizing hormone after oxytocin infusion in men.

Plasma oxytocin (OT), FSH, and LH were measured by specific RIA in eight healthy adult males before, during, and after stopping iv infusions of OT. With a constant infusion of 132 mU OT/min for 60 min, plasma OT reached a steady state concentration of 228-241 pg/ml at 30-60 min. When the dose of oxytocin infused was doubled every 15 min, plasma OT increased from 81.0 +/- 17.9 pg/ml (mean +/- SE) with 32 mU/min to reach a steady state concentration of 378 +/- 73.4 pg/ml with 256 mU/min (1 muU = 2 pg OT). The curve of disappearance of plasma OT could be resolved into a single exponential curve in all of the subjects, with a mean calculated half-life of 10.3 +/- 1.6 min (range, 5.3-17.3 min). The mean MCR of OT was 21.5 +/- 3.3 ml/kg.min, and the mean apparent volume of distribution was 305 +/- 46 ml/kg. Plasma FSH and LH showed no significant change throughout OT infusion and for up to 60 min after stopping the OT infusion. The findings demonstrate that in man 1) plasma OT concentration achieved is closely related to the infusion rate, 2) OT infusion does not affect plasma FSH and LH, and 3) the apparent volume of distribution of OT suggests that infused OT is distributed into space or spaces other than the circulating plasma volume.

Expression of gap junction protein connexin-43 in the human and baboon (Papio anubis) corpus luteum.

In the nonhuman primate and human corpora lutea, gap junctions have been identified by means of electron microscopy. Gap junctions are formed by connexons, which consist of a multigene family of tissue-specific connexins. In the ovarian follicle, the gap junction protein connexin-43 is present and hormonally regulated. However, there is little evidence indicating the type of connexin present in the corpus luteum. Therefore, the aim of this study was to demonstrate the presence of gap junctions by electron microscopy and the presence of connexin-43 and messenger ribonucleic acid (mRNA) for this protein. Using immunocytochemical procedures, we have shown the presence of connexin-43 in baboon and human midluteal phase corpora lutea and in the atretic corpora lutea of the baboon. The intensity of immunoreactivity was lower in atretic corpora lutea than in the midluteal phase corpora lutea. Western analysis indicates the presence of two bands at 43-45 kDa, and that the levels of connexin-43 protein are abundant in the midluteal phase. The two bands suggest the presence of the protein in a phosphorylated or a nonphosphorylated form. Ribonuclease protection assay suggests that the mRNA levels of connexin-43 remain constant throughout the luteal phase. mRNA for connexin-43 was not detectable in atretic corpora lutea. Thus, connexin-43 is one of the connexin family of proteins forming the connexon of gap junctions in the baboon and human corpus luteum. The expression of the protein may be hormonally regulated by locally produced factors, such as estradiol and progesterone. We suggest that gap junctional communication between the cells of the primate and human corpus luteum may be important in hormone synthesis and secretion and may be involved in the process of luteolysis through luteal cell apoptosis.

Epidermal growth factor receptors in uteroplacental tissues in term pregnancy before and after the onset of labor.

Using saturation binding assays and Scatchard analyses, we determined the concentrations and binding affinities of epidermal growth factor (EGF) receptors in human myometrium (n = 13) and decidua (n = 10) before and during labor and in placenta (n = 15), chorion (n = 17), and amnion (n = 17) before labor, during labor, and after vaginal delivery. Each tissue was individually assayed. In myometrium and chorion, EGF receptors increased significantly from 5.6 +/- 0.8 and 13.5 +/- 1.7 fmol/mg protein (mean +/- SEM) before labor to 11.1 +/- 2.8 and 26.7 +/- 3.0 fmol/mg protein, respectively, after the onset of labor (P < 0.05). In amnion, EGF receptors increased from 12.8 +/- 2.7 fmol/mg protein before labor to 33.0 +/- 2.3 fmol/mg protein during labor, but decreased significantly (5.9 +/- 1.2 fmol/mg protein) with vaginal delivery (P < 0.05). Decidual and placental concentrations of EGF receptors did not change significantly with labor. The binding affinity of EGF receptors in all tissues studied did not change significantly with labor, as reflected by their respective association and dissociation constants. Up-regulation of EGF receptors in myometrium, chorion, and amnion with spontaneous labor may enhance stimulation of prostanoid production and stimulate uterine activity.

Human corpus luteum: luteinizing hormone and chorionic gonadotropin receptors during the menstrual cycle.

To characterize and determine the concentration of LH/hCG receptors in human corpora lutea of the menstrual cycle, we measured occupied and unoccupied receptors and determined the association (Ka) and dissociation (Kd) constants individually in 23 corpora lutea (CL) and 4 corpora albicantia obtained at the time of tubal ligation from 25 normal cycling women. We found no [125I]hCG binding in any of the corpora albicantia. Scatchard plot analysis for each CL revealed a linear binding plot indicative of a single set of LH/hCG receptors. The mean concentration of unoccupied receptors was 36 +/- 10 (+/- SE) fmol/mg protein in the early luteal phase (days 15-19; n = 5), 64 +/- 11 fmol/mg protein in the midluteal phase (days 20-25; n = 13), and 42 +/- 19 fmol/mg protein in the late luteal phase (days 26-30; n = 5). The concentrations of occupied receptors were 56 +/- 8, 46 +/- 6, and 54 +/- 12 fmol/mg protein in the early, mid-, and late luteal phases, respectively. Total (occupied plus unoccupied) receptor concentrations reached maximum levels of 110 +/- 11 fmol/mg protein in the midluteal phase. Ka increased progressively from 12 +/- 4 X 10(9) mol/L-1 in the early luteal phase to 19 +/- 7 X 10(9) and 21 +/- 8 X 10(9) mol/L-1 in the mid- and late luteal phases. We conclude that in normal CL, 1) total and unoccupied LH/hCG receptor levels parallel progesterone secretion; 2) changes in the binding affinity may be important in sustaining and/or rescuing the CL; and 3) loss of LH/hCG receptors is probably related to luteolysis.

The effect of naloxone on endogenous opioid regulation of pituitary gonadotropins and prolactin during the menstrual cycle.

To determine the influence of ovarian sex steroid hormones on endogenous opioid regulation of pituitary FSH, LH, and PRL secretion, six women were studied during the follicular phase (days 8-9) and luteal phase (days 21-23) of their menstrual cycles. An iv bolus dose of 10 mg of the opiate antagonist naloxone was given, and plasma FSH, LH, and PRL were measured at -30, -15, 0, 15, 30, 45, 60, 90, 120, and 180 min. During the follicular phase, baseline plasma FSH and LH levels were 10.7 +/- 0.9 and 16.7 n+/- 2.0 mIU/ml (mean +/- SEM), respectively; the plasma PRL level was 11.7 +/- 1.2 ng/ml. Naloxone did not significantly alter plasma FSH, LH, or PRL during the follicular phase. Basal levels of LH were significantly lower during the luteal phase than during the follicular phase (P less than 0.01). During the luteal phase, plasma LH increased significantly from a basal level of 10.0 +/- 1.0 to 20.8 +/- 3.0 mIU at 30 min (P less than 0.001) and remained significantly elevated at 90 min. Similarly, plasma PRL increased significantly from a basal level of 11.0 +/- 0.7 to 16.2 +/- 2.7 ng/ml at 30 min (P less than 0.025), but decreased by 90 min to 12.5 +/- 1.5 ng/ml. Plasma FSH did not change after naloxone treatment. Our results suggest that endogenous opiates have a prominent inhibitory effect on pituitary gonadotropin and PRL secretion only during the luteal phase of the menstrual cycle.

Oxytocin release and plasma anterior pituitary and gonadal hormones in women during lactation.

Serial plasma oxytocin (OT), PRL, TSH, FSH, LH, estrone, estradiol, and progesterone were measured by RIA in 12 women before and during a 30-min breast-feeding period on the third or fifth postpartum day. Plasma OT increased significantly from 10.8 +/- 3.4 to 22.4 +/- 3.5 pg/ml (mean +/- SE) within 2 min of suckling (P = less than 0.05) to reach the mean peak level of 53.2 pg/ml at 10 min. The increase in plasma OT was bimodal. Plasma PRL and TSH also increased significantly from baseline levels of 192 +/- 39 ng/ml and 16.9 +/- 5.6 microU/ml, respectively, to reach maximum levels of 427 +/- 91 ng PRL/ml at 10 min (P = less than 0.025) and 281.5 +/- 56.6 microU TSH/ml at 25 min (P = less than 0.005). Plasma FSH-beta (range of means, 3.5-4.6 ng/ml), LH (range of means, 1.7-2.6 mIU/ml), and estradiol (range of means, 29.8-38.2 pg/ml) were low and remained unchanged throughout breast feeding. Plasma progesterone was 6.0 +/- 0.4 ng/ml before breast feeding and did not alter significantly during breast feeding. The significance of these findings is discussed in relation to the milk let-down reflex and the relationship of TSH to PRL.

Interleukin-1 beta induces cyclooxygenase-2 gene expression in cultured endometrial stromal cells.

Increasing evidence indicates that PGs may play an obligatory role in blastocyst implantation. Cyclooxygenase (also known as PGH synthase) isozymes 1 and 2 catalyze the rate limiting steps in the biosynthesis of PGs. The ubiquitous cyclooxygenase-1 (COX-1) subserves housekeeping functions, whereas the inducible cyclooxygenase-2 (COX-2) is expressed by limited cell types and tightly controlled. Here we report the induction of COX-2 gene expression by interleukin-1 beta (IL-1 beta) in cultured human endometrial stromal cells. COX-2 activity was induced by IL-1 beta (1 ng/mL); conversion of exogenous arachidonic acid to PGF2 alpha increased from 2.6 +/- 0.6 ng/well (mean +/- SEM; n = 6) to 22.2 +/- 5.6 ng, but was completely blocked (2.8 +/- 0.7 ng/well) by NS-398, a specific COX-2 inhibitor. Undetectable in quiescent stromal cells, messenger ribonucleic acid for COX-2 was induced 30 min after IL-1 beta treatment, reached a maximum at 4 h, and decreased after 15 h. Protein synthesis was not required for induction of the COX-2 gene, as it was blocked by actinomycin D but not by cycloheximide. The 70-kDa COX-2 protein was not detected in quiescent cells, became detectable 6 h after IL-1 beta treatment, and remained detectable even after 15 h. IL-1 beta (0.1-100 ng/mL) increased the luciferase activity in promoterless luciferase reporter containing the 900-bp 5'-flanking sequence (-891 to +9) of the COX-2 gene in a dose-dependent manner, with an ED50 of 0.1-1 ng/mL.

Human corpus luteum secretion of relaxin, oxytocin, and progesterone.

To determine whether the human corpus luteum is a source of relaxin and oxytocin, we measured the concentrations of these peptides in plasma obtained from the ovarian veins of ovaries with and without a corpus luteum and compared these to peripheral plasma levels. Peripheral and ovarian venous blood samples were obtained from 34 nonpregnant women, 13 during the luteal phase and 21 during the follicular phase of their cycles, and from a 6-week pregnant woman. Plasma relaxin, oxytocin, and progesterone concentrations were determined by sensitive and specific RIAs. Plasma relaxin levels were not detectable (less than 0.16 microgram/L) in peripheral or ovarian venous plasma not draining a corpus luteum. The mean relaxin concentration in plasma draining an ovary with a corpus luteum was 0.41 +/- 0.09 (+/- SE) microgram/L. Oxytocin levels also were significantly higher in plasma draining an ovary with a corpus luteum (6.70 +/- 1.86 pmol/L) than in that draining the ovary with no corpus luteum (1.58 +/- 0.09 pmol/L; P less than 0.01) or in peripheral plasma (1.58 +/- 0.09 pmol/L; P less than 0.025). The mean progesterone concentration also was highest in plasma draining an ovary with a corpus luteum (210.2 +/- 50.5 nmol/L) compared with those in plasma from the contralateral ovarian vein (40.3 +/- 16.5 nmol/L P less than 0.005) and peripheral plasma (30.2 +/- 5.7 nmol/L; P less than 0.005) during the luteal phase. In a woman who was 6 weeks pregnant, plasma draining the ovary with a corpus luteum had 1.9 micrograms relaxin/L, but only 0.49 pmol/L oxytocin; the latter was similar to concentrations in noncorpus luteum-bearing ovarian venous plasma. These findings indicate that the human corpus luteum secretes relaxin, oxytocin, and progesterone. Both ovarian oxytocin and relaxin may function as paracrine or autocrine modulators of luteal function.

Nonsteroidal anti-inflammatory drugs and changing attitudes toward dysmenorrhea.

Dysmenorrhea, which may be primary or secondary, is the occurrence of painful uterine cramps during menstruation. Until a decade ago, medical and social attitudes toward dysmenorrhea were shrouded with folklore, psychoanalytical profiles, or psychosomatic bases. In secondary dysmenorrhea, there is a visible pelvic lesion to account for the pain, whereas only a biochemical abnormality is responsible for primary dysmenorrhea. Recent advances in the biochemistry of prostaglandins and their role in the pathophysiology of primary dysmenorrhea and intrauterine device (IUD)-induced dysmenorrhea have now firmly established a rational basis for the disorder. In primary dysmenorrhea, menstrual prostaglandin release is significantly increased but can be readily suppressed to normal levels when nonsteroidal anti-inflammatory drugs (NSAIDs) capable of inhibiting cyclo-oxygenase are given during menstruation. Many clinical trials (controlled and uncontrolled) have demonstrated the efficacy of NSAIDs such as the fenamates, indole-acetic acid derivatives, and arylpropionic acid derivatives in relieving primary dysmenorrhea as well as IUD-induced dysmenorrhea that is also due to elevated prostaglandin levels. With a few of these NSAIDs, it has been shown that the relief of pain is associated with a significant decrease in menstrual fluid prostaglandin levels. Cumulative data of clinical trials indicate that with the effective NSAIDs, 80 percent of patients with significant primary dysmenorrhea can be adequately relieved. Ongoing studies suggest that in some women, endometrial leukotriene, but not PGF2a production, is increased. With the official approval and availability of several effective NSAIDs for the specific treatment of primary dysmenorrhea in the United States, women who have primary dysmenorrhea have been greatly relieved and their productivity increased. Primary dysmenorrhea affects 50 percent of postpubescent women and absenteeism among the severe dysmenorrheics has been estimated to cause about 600 million lost working hours or 2 billion dollars annually. Thus, an effective, simple, and safe treatment of primary dysmenorrhea for two to three days during menstruation will not only have a positive economic impact but will also enhance the quality of life. The availability of effective dysmenorrhea therapy with NSAIDs has induced greater expectations of relief by the patient, as well as greater willingness to seek medical help, a more rational approach to patient management by physicians, changes in attitude toward women with primary dysmenorrhea, and the debunking of myths about dysmenorrhea that often have been perpetuated as fact.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: The availability of effective dysmenorrhea therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) has been accompanied by greater expectations of relief on the part of the patient, increased willingness to seek medical help, a more rational approach to patient management by physicians, changes in attitude toward women with primary dysmenorrhea, and a debunking of the myths associated with dysmenorrhea. Following a review of the prevalence, social and economic impact, and the nonmedical myths surrounding dysmenorrhea, attention focuses on the cause and clinical diagnosis of dysmenorrhea and the therapeutic use of NSAIDS. NSAIDs Relief can be obtained in 80-85% of patients studied, with NSAIDs shown to be clinically effective against primary dysmenorrhea. Several NSAIDs have been shown to relieve primary dysmenorrhea through the suppression of menstrual fluid prostaglandins. Primary dysmenorrhea now is more often diagnosed on the basis of its positive features rather than by the exclusion of other disorders as was previously the case. As yet, it is unclear as to why 15-20% of patients fail to have an adequate response to NSAIDs. As patients can obtain effective relief from primary dysmenorrhea from treatment with the appropriate NSAID, there is a significant impact on work productivity, absenteeism, economic loss, social adjustment, and patient attitude toward menstruation and medical help.

Ibuprofen and dysmenorrhea.

Primary dysmenorrhea and secondary dysmenorrhea induced by an intrauterine device are associated with increased production and release of endometrial prostaglandins. The condition may be treated by oral contraceptives, which reduce overall menstrual fluid volume, or by a prostaglandin synthetase inhibitor, such as ibuprofen. Unless the patient wishes to use oral contraceptives for birth control, ibuprofen (Motrin) is the drug of choice because it need only be given for two to three days each cycle, does not suppress the pituitary ovarian axis, and does not cause metabolic alterations. Clinical trials have shown ibuprofen to be highly efficacious, and more effective than indomethacin, aspirin, or propoxyphene, with no or few side effects.

Prostaglandins in primary dysmenorrhea. Comparison of prophylactic and nonprophylactic treatment with ibuprofen and use of oral contraceptives.

Prostaglandin synthetase inhibitors have been used in clinical trials for the treatment of primary dysmenorrhea on the theory that the disorder may be caused by a high level of prostaglandins. However, a causal role of prostaglandin in dysmenorrhea has not been established, and there is only indirect evidence that the amelioration of dysmenorrhea by prostaglandin synthetase inhibitors is related to their inhibition of prostaglandin synthesis in the uterus. We, therefore, monitored menstrual prostaglandin release in 14 dysmenorrheic patients in a controlled, double-blind, cross-over trial of ibuprofen (Motrin) and in two dysmenorrheic subjects while they were receiving oral contraceptive therapy and while they were not. A total of 89 menstrual cycles were studied. We found that ibuprofen therapy reduced menstrual prostaglandin release and relieved dysmenorrhea but that placebo therapy did not. Oral contraceptives decreased menstrual flow, reduced prostaglandin release and also alleviated dysmenorrhea. We conclude that primary dysmenorrhea is related to a high level of menstrual prostaglandin release. Ibuprofen inhibits prostaglandin synthesis whereas oral contraceptives inhibit ovulation and cyclic endometrial development. Thus, the two drugs suppress endometrial prostaglandin through different mechanisms. Reduction of menstrual prostaglandin release leads to alleviation of dysmenorrhea.

Feasibility of maintaining normal glucose profiles in insulin-dependent pregnant diabetic women.

This study was designed to test the feasibility of a patient-monitored glucose determination program to establish and maintain normal blood glucose levels. Ten pregnant women, who were insulin-dependent diabetics prior to becoming pregnant and who were in their eighth week or less of pregnancy, were offered the program. All 10 accepted and continued the program for the duration of their pregnancy. Normal plasma glucose (60 to 140; mean = 80 mg/dl) levels were achieved after one week of the program and were maintained throughout the pregnancy as documented by 5 to 8 blood glucose determinations a day. The hemoglobin A1c level, which was elevated in all 10 patients at the start (9.4 +/- 1.6 per cent) of the program, fell into the normal range (2 to 5.0 per cent) five weeks after glucose values became normal. Serum estradiol (0.8 +/- 0.6 ng/ml), serum prolactin (10 +/- 9 ng/ml) and serum human chorionic gonadotropin (5,500 +/- 1,700 ng/ml), although all abnormal at the start of the program, became normal after glucose control was achieved (program weeks 4, 5 and 6, respectively). The infants showed no signs of macrosomnia (2,988 +/- 959 g), hypoglycemia, hyperbilirubinemia, hypocalcemia, erythremia or respiratory distress. Therefore, a program to maintain normal blood glucose levels during a diabetic patient's pregnancy is not only possible but may also improve the pregnancy and the outcome.

Immunohistological localization and expression of alpha-actin in the baboon (Papio anubis) corpus luteum.

We have recently shown the presence of E-cadherin and of alpha- and gamma-catenins in human and baboon corpora lutea. These are components of adherens junctions between cells. The cytoplasmic catenins link the cell membrane-associated cadherins to the actin-based cytoskeleton. This interaction is necessary for the functional activity of the E-cadherins. Our aim therefore was to determine the presence of alpha-actin in the baboon corpus luteum, to further establish whether the necessary components for E-cadherin activity are present in this tissue. An antibody specific for the smooth muscle isoform of actin, alpha-actin, was used for these studies. The results using immunohistochemistry show that (a) alpha-actin is present in steroidogenic cells of the active corpus luteum, theca externa of the corpus luteum, cells of the vasculature, and the tunica albuginea surrounding the ovary. The intensity of immunoreactivity for alpha-actin varied, with the cells of the vasculature reacting more intensely than the luteal cells. A difference in intensity of immunoreactivity was also observed among the luteal cells, with the inner granulosa cells showing stronger immunoreactivity than the peripheral theca lutein cells. There was no detectable immunoreactivity in the steroidogenic cells of the atretic corpus luteum. However, in both the active and atretic corpora lutea, alpha-actin-positive vascular cells were dispersed within the tissue. (b) Total alpha-actin (luteal and non-luteal), as determined by Western blot analyses, does not change during the luteal phase and subsequent corpus luteum demise (atretic corpora lutea). (c) hCG stimulated the expression of alpha-actin and progesterone secretion by the early luteal phase (LH surge + 1-5 days) and mid-luteal phase (LH surge + 6-10 days) cells in culture, but only progesterone in the late luteal phase (LH surge + 11-15 days). The data show that alpha-actin is present in luteal cells and that its expression is regulated by hCG, thus suggesting that E-cadherin may form functional adherens junctions in the corpus luteum.