Efficacy and safety of a transdermal contraceptive system.

OBJECTIVES: To evaluate the efficacy, cycle control, compliance, and safety of a transdermal contraceptive system that delivers norelgestromin 150 microg and ethinyl estradiol 20 microg daily. METHODS: In this open-label, 73-center study, 1672 healthy, ovulatory, sexually active women received ORTHO EVRA/EVRA for six (n = 1171) or 13 cycles (n = 501). The treatment regimen for each cycle was three consecutive 7-day patches (21 days) followed by 1 patch-free week. RESULTS: The overall and method-failure probabilities of pregnancy through 13 cycles were 0.7% and 0.4%, respectively. The incidence of breakthrough bleeding was low throughout the study. Perfect compliance (21 consecutive days of dosing, followed by a 7-day drug-free interval; no patch could be worn for more than 7 days) was achieved in 90% of subject cycles; only 1.9% of patches detached completely. Adverse events were typical of hormonal contraception, and most were mild-to-moderate in severity and not treatment limiting. The most common adverse events resulting in discontinuation were application site reactions (1.9%), nausea (1.8%), emotional lability (1.5%), headache (1.1%), and breast discomfort (1.0%). CONCLUSIONS: The transdermal contraceptive patch provides effective contraception and cycle control, and is well tolerated. The weekly change schedule for the contraceptive patch is associated with excellent compliance and wearability characteristics.

Prevention of vaginal trichomoniasis by compliant use of the female condom.

BACKGROUND: Several case-control studies suggest that the male condom protects women against some sexually transmitted diseases. The female condom is the first barrier device under the woman's control that may be effective in the prevention of sexually transmitted diseases. GOAL OF THIS STUDY: To determine if appropriate use of the female condom decreased the rate of recurrent vaginal trichomoniasis in previously diagnosed and treated women. STUDY DESIGN: One hundred and four sexually active women with vaginal trichomoniasis were treated with metronidazole and assigned to a group using the female condom or a control group during a 45-day period of continued sexual activity. Fifty women served as controls, and 54 women were assigned to use the female condom. RESULTS: Only 20 women used the female condom each time they had sexual intercourse. Reinfection with trichomonas occurred in 7/50 (14%) controls, in 5/34 (14.7%) noncompliant users, and in 0/20 compliant users of the female condom. CONCLUSION: The compliant use of the female condom is effective in preventing recurrent vaginal trichomoniasis.

PIP: Gynecologists used a single 2 gm oral dose of metronidazole to treat 104 sexually active women (= or 18 years old) for vaginal trichomoniasis as part of a study to determine whether the female condom, when used properly, can protect against reinfection. They counseled the women about the risk of reinfection and to use barrier protection to prevent reinfection. The study took place at urban medical centers in New Haven, Connection; Lose Angeles, California; Chicago, Illinois; and Richmond, Virginia. 50 women, who said they would not use the female condom every time they engaged in coitus during the next 45 days, comprised the control group. Cases were divided into compliant and noncompliant users (N = 20 and 34, respectively). Noncompliant users did not use barrier protection during at least 1 sexual intercourse (mean = 5.1 times). None of the compliant users experienced recurring vaginal trichomoniasis, while 14.7% (5) of noncompliant users and 14% (7) of controls did (p = .09 and .08, respectively). Further, the number of genital contacts (e.g., pre-ejaculatory coitus) before inserting the female condom was much higher in the noncompliant users reinfected with vaginal trichomoniasis than it was in noncompliant users not reinfected (12.25 vs. 4.23; p = .03). In addition, the controls had essentially the same number of unprotected genital contacts as did the noncompliant users (12.1 and 12.25, respectively). These findings suggested that a dose-response relationship exists between female condom use and number of unprotected genital contacts. They also demonstrated that compliant use of the female condom protects against recurrent vaginal trichomoniasis. Further studies should examine whether compliant use of the female condom also protects against gonorrhea, chlamydia, and other sexually transmitted diseases.

Nitrendipine and omega-conotoxin modulate gonadotropin release and gonadotrope [Ca2+]i.

We have examined the pharmacology of the voltage-sensitive Ca2+ channels (VSCCs) that mediate gonadotropin secretion from primary cultures of rat pituitary cells, stimulated by either cell depolarization or by binding of gonadotropin-releasing hormone (GnRH). We also measured single-cell [Ca2+]i transients using fura-2 in gonadotropes identified by a reverse hemolytic plaque assay employing an antiserum to luteinizing hormone (LH). Cell depolarization evoked by either 50 mM K+ or 30 microM veratridine induced 2- to 6-fold increases in gonadotropin secretion over basal levels. GnRH caused 6- to 20-fold increases in follicle-stimulating hormone (FSH) and LH secretion, respectively, with maximal stimulation at 100 nM GnRH. K(+)- or GnRH-induced FSH release was largely prevented by co-incubation with 1 mM CdCl. Tetrodotoxin (TTX, 5 microM) prevented the veratridine-, but not the K(+)- or GnRH-induced, stimulation of FSH secretion. Nitrendipine (Ntd, 1 microM) produced 35-50% inhibition (NS) of both FSH and LH release stimulated by either 50 mM K+ or 100 nM GnRH. Ntd also inhibited the K(+)-induced [Ca2+]i rise (greater than 90%), as well as the secondary, plateau phase of the GnRH-induced elevation of [Ca2+]i (100% inhibition). Omega-conotoxin (omega-CgTx, 100 nM) partially suppressed FSH and LH release (NS) due to both K+ (33% each) and GnRH (44% and 18%, respectively). omega-CgTx showed variable effects on [Ca2+]i transients evoked by K+ or GnRH ranging from clear inhibition to no effect. We conclude that influx of extracellular Ca2+ is one of several fundamental events underlying the depolarization- or receptor-activated release of LH and FSH, and that this influx can be inhibited by dihydropyridine-sensitive ('L') Ca2+ channels. Two classes of L-channels may exist in gonadotropes, that differ in their sensitivity to omega-CgTx.

Treatment of infertility due to retrograde ejaculation: a simple, cost-effective method.

Our data indicate that an appropriate therapy for the infertility associated with retrograde ejaculation is isolation of sperm from voided urine after orgasm, plus IUI. This technique is simple and can be performed in the physician's office, in contrast to more complex techniques such as GIFT or in vitro fertilization.

Direct neuropeptide Y-induced modulation of gonadotrope intracellular calcium transients and gonadotropin secretion.

Neuropeptide Y (NPY) has been shown to be capable of both the enhancement and suppression of gonadotropin secretion from pituitary cells. In order to elucidate the underlying cellular mechanisms which might account for these actions, we have examined the effects of NPY on gonadotropin secretion stimulated by either cell depolarization or by GnRH from primary cultures of rat pituitary cells. In one set of experiments, we measured single-cell [Ca2+]i using the Ca2(+)-sensitive intracellular fluorescent indicator Fura-2, in gonadotropes which had been identified using a reverse hemolytic plaque assay employing an antiserum to LH. In another group of investigations, we measured FSH and LH secretion in response to depolarization or stimulation with GnRH, and examined the influence of NPY on these patterns of secretion. NPY was active in inhibiting the amplitude of the [Ca2+]i signal induced by depolarization with 20 mM K+, as well as in substantially blocking the secondary plateau phase of the GnRH-induced elevation of [Ca2+]i. However, the peak [Ca2+]i transients occurring in response to either depolarization with 50 mM K+ or the initial phase of the GnRH-induced response, were not sensitive to blockade by NPY. Moreover, treatment of the cells for 24 h with pertussis toxin prevented the NPY-mediated inhibition of the GnRH-stimulated [Ca2+]i plateau. Cell depolarization by 50 mM K+ induced 3-fold increases in FSH and LH release over 2-h incubations. GnRH (100 nM) elicited a 9-fold increase in FSH and a 14-fold stimulation of LH over the same time period. NPY had insignificant effects upon depolarization-induced hormone release, but at 1 microM partially suppressed LH release elicited by 100 nM GnRH over 2 h. We conclude that NPY is capable of inhibiting [Ca2+]i signals in gonadotropes that are stimulated by GnRH, and that these effects are mediated through activation of a pertussis toxin-sensitive G-protein. These effects on [Ca2+]i may underly the inhibitory effects of NPY on gonadotropin secretion.

DNA analysis of unilateral twin ectopic gestation.

Although the overall incidence of ectopic gestation has been rising over the past 30 years, unilateral twin tubal gestation is still a relatively rare event. In the 93 cases reported to date, zygosity determined solely by subjective observations of the fetuses indicated monozygosity in more than 95%. We report a case of unilateral twin tubal gestation in which zygosity of the twins was determined by using DNA probes that detect restriction fragment length polymorphisms. We used six human DNA probes and M13 phage DNA to compare the genotypes of the twins. Three of the six human probes and the M13 probe showed differences, proving that these twins were dizygotic. We speculate that many of the unilateral ectopic twins who were thought to be monozygotic may actually have been dizygotic.

The role of exogenous calcium for gonadotropin-stimulated progesterone production by human granulosa-luteal cells.

Previous studies of cells from various species have indicated that exogenous calcium is necessary for gonadotropic stimulation of steroidogenesis. To determine whether this requirement for exogenous calcium is a universal attribute of steroidogenic cells, we studied baseline and stimulated progesterone (P) production by cultured human granulosaluteal cells obtained at the time of oocyte retrieval for in vitro fertilization (IVF). During 4 hours in culture, both cholera toxin (1.25 micrograms/mL) and human chorionic gonadotropin (hCG, 1 IU/mL) stimulated a significant (P less than 0.05) 2- to 4-times increase in P production. Both baseline and stimulated (cholera toxin or hCG) increases in P were unaffected when cellular uptake of exogenous calcium was inhibited by the calcium channel blocker nitrendipine (10 microM), or by culturing the cells in calcium-free medium or in calcium-free medium with [ethylenebis(oxyethylenenitrilo)]-tetra-acetic acid (EGTA, to chelate any possible free extracellular calcium). At later time points (24 and 48 hours), lack of available exogenous calcium began to have an inhibitory effect on P production, and the hCG effect was more sensitive to the lack of exogenous calcium than was the cholera toxin effect. We speculate that this apparent independence from exogenous calcium over a short culture period is due to the prior stimulation of these cells by exogenous gonadotropins employed in IVF cycles.

Gonadotropin-releasing hormone-induced Ca2+ transients in single identified gonadotropes require both intracellular Ca2+ mobilization and Ca2+ influx.

We examined the effects of gonadotropin-releasing hormone (GnRH) on the intracellular free Ca2+ concentration ([Ca2+]i) in single rat anterior pituitary gonadotropes identified by a reverse hemolytic plaque assay. Concentrations of GnRH greater than 10 pM elicited increases in [Ca2+]i in identified cells but not in others. In contrast, depolarization induced by 50 mM K+ increased [Ca2+]i in all cells. Ca2+ transients induced by GnRH exhibited a complex time course. After an initial rapid rise, the [Ca2+]i fell to near basal levels only to be followed by a secondary extended rise and fall. Analysis of the Ca2+ transients on a rapid time base revealed that responses frequently consisted of several rapid oscillations in [Ca2+]i. Removal of extracellular Ca2+ or addition of the dihydropyridine Ca2+-channel blocker nitrendipine completely blocked the secondary rise in [Ca2+]i but had no effect whatsoever on the initial spike. Nitrendipine also blocked 50 mM K+-induced increases in [Ca2+]i in identified gonadotropes. The secondary rise induced by GnRH could be enhanced by a phorbol ester in a nitrendipine-sensitive fashion. Multiple spike responses to GnRH stimulation of the same cell could only be obtained if subsequent Ca2+ influx was permitted either by allowing a secondary rise to occur or by producing a Ca2+ transient by depolarizing the cells with 50 mM K+. It therefore appears that the response to GnRH consists of an initial phase of Ca2+ mobilization, probably mediated by inositol trisphosphate, and a subsequent phase of Ca2+ influx through nitrendipine-sensitive Ca2+ channels that may be activated by protein kinase C. The relative roles of these phases in the control of gonadotropin secretion are discussed.

Preservation of fertility in women with pelvic inflammatory disease.

The epidemic of sexually transmitted diseases has placed young, sexually active women at risk of infertility from tubal and pelvic factors. Salvaging reproductive function in women desiring fertility depends upon an accurate diagnosis and early, aggressive therapy for all cases of salpingitis. Conservative surgical management of tubal pregnancy in such women is now standard practice. Less-aggressive surgical approaches to chronic pelvic inflammatory disease and even tuboovarian abscess, when possible, can preserve some part of the pelvic anatomy in these women, who may then undergo reconstructive pelvic surgery or in vitro fertilization. Due to the recent technological revolution in infertility therapy, preservation of a women's uterus alone is all that is necessary to sustain the hope for a pregnancy.

Variability and selectivity of anterior pituitary response to dopamine agonists throughout the normal menstrual cycle.

To clarify whether there is a variation of dopamine effect throughout the normal menstrual cycle, 24 studies were performed during the follicular, periovulatory, and luteal phase in seven ovulatory women. The subjects were studied for 24 hours after receiving two different dopamine agonists, 2.5 mg of bromocriptine in one cycle and 50 micrograms of pergolide in a subsequent cycle. Baseline plasma luteinizing hormone, follicle-stimulating hormone, prolactin, and thyrotropin were followed through time, and the dynamic responses to gonadotropin-releasing hormone and thyrotropin-releasing hormone before and at 6 and 22 hours after medication were studied. Since the results obtained with both agonists were similar, the data have been combined in a single group. Baseline luteinizing hormone levels (but not follicle-stimulating hormone) were significantly suppressed (p less than 0.01) during the follicular phase only, and the plasma luteinizing hormone and follicle-stimulating hormone response to gonadotropin-releasing hormone was not affected by the agonists in any of the three cycle phases. Baseline plasma prolactin was suppressed equally (p less than 0.005) in all phases of the cycle, and the response to thyrotropin-releasing hormone was similarly suppressed in all phases only at 6 hours (p less than 0.002). Baseline thyrotropin also was suppressed (p less than 0.01) in all phases but the degree of inhibition was greater in the luteal than in the follicular phase (p less than 0.05). The response to thyrotropin-releasing hormone was inhibited, with the smallest response seen at 22 hours (p less than 0.01). In conclusion, these results suggest that the modulatory effect of dopamine on pituitary hormone secretion is variable and selective throughout the normal menstrual cycle. The greatest inhibition is on prolactin release, which is similar in all phases, followed by thyrotropin, which is greater in the luteal phase, and then by luteinizing hormone in the follicular phase only; it has no effect on follicle-stimulating hormone release.

Characterization of voltage-sensitive calcium channels in a clonal pituitary cell line.

We have pharmacologically characterized voltage sensitive calcium channels (VSCCs) in GH3 cells, an anterior pituitary clonal cell line known to secrete prolactin and growth hormone. Raising the medium K+ concentration from 5 to 50 mM caused an immediate increase in net 45Ca2+ uptake which remained apparent over a 15 minute time course. 45Ca2+ uptake was maximally stimulated nearly 10-fold over basal levels. This K+-induced stimulation of Ca2+ uptake was not prevented by 10-5M tetrodotoxin or by replacing sodium with choline in the assay medium. Ca2+ uptake was, however, inhibited by several VSCC antagonists: nitrendipine, D-600, diltiazem and Cd2+. Further, the novel dihydropyridine VSCC agonists, BAY K8644 and CGP 28392, enhanced 50 mM K+-stimulated 45Ca2+ uptake and these effects were blocked by nitrendipine.

Hyperprolactinemia: comparison of thyrotropic-releasing hormone and tomography.

A group of 95 women with unexplained hyperprolactinemia (over 20 ng/mL) underwent radiologic examination of the sella turcica with hypocycloidal polytomography (N = 58), computed axial tomography (N = 8), or both (N = 29). All patients also underwent a thyrotropin-releasing hormone (TRH) stimulation test, with serum prolactin (PRL) measurement before and 20 and 30 minutes after a 500-micrograms intravenous bolus of TRH. Their PRL responses were compared with those of two control groups, nine normal women in the follicular phase of the menstrual cycle, and 13 women in the first five months of gestation with pregnancy-related hyperprolactinemia. Both control groups exhibited PRL increases with 95% confidence limits at least 200% above baseline levels. In all, 12 patients from the study group also had a normal PRL response (more than a 200% increase) to TRH, and none of these women had tomographic findings consistent with a pituitary tumor. The remaining 83 women all had diminished or absent PRL increases after TRH administration; 46 (55%) of these patients had radiographic evidence of an adenoma, whereas 37 (45%) had no clear signs of a tumor on either polytomography or computed axial tomography. No patient with a baseline PRL level in excess of 60 ng/mL had a normal PRL response to TRH. The results of the study indicate that 1) in patients with PRL between 20 and 60 ng/mL, a normal TRH test can be relied upon to avoid the expense and radiation of tomography (computed axial tomography or polytomography), 2) there is no benefit to be obtained in performing a TRH test in patients with a baseline PRL level over 60 ng/mL, and 3) about 45% of patients with hyperprolactinemia and an abnormal TRH test have a normal computed tomography or polytomography. These patients may have a small adenoma, and thus warrant closer follow-up than patients with a normal TRH test.