Estradiol-Responsive miR-365a-3p Interacts with Tissue Factor 3'UTR to Modulate Tissue Factor-Initiated Thrombin Generation.

BACKGROUND: High estradiol (E2) levels are linked to an increased risk of venous thromboembolism; however, the underlying molecular mechanism(s) remain poorly understood. We previously identified an E2-responsive microRNA (miR), miR-494-3p, that downregulates protein S expression, and posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner via miRs. OBJECTIVES: To evaluate the coagulation capacity of cohorts with high physiological E2, and to further characterize novel E2-responsive miR and miR regulation on tissue factor in E2-related hypercoagulability. METHODS: Ceveron Alpha thrombin generation assay (TGA) was used to assess plasma coagulation profile of three cohorts. The effect of physiological levels of E2, 10 nM, on miR expression in HuH-7 cells was compared using NanoString nCounter and validated with independent assays. The effect of tissue factor-interacting miR was confirmed by dual-luciferase reporter assays, immunoblotting, flow cytometry, biochemistry assays, and TGA. RESULTS: Plasma samples from pregnant women and women on the contraceptive pill were confirmed to be hypercoagulable (compared with sex-matched controls). At equivalent and high physiological levels of E2, miR-365a-3p displayed concordant E2 downregulation in two independent miR quantification platforms, and tissue factor protein was upregulated by E2 treatment. Direct interaction between miR-365a-3p and F3-3'UTR was confirmed and overexpression of miR-365a-3p led to a decrease of (1) tissue factor mRNA transcripts, (2) protein levels, (3) activity, and (4) tissue factor-initiated thrombin generation. CONCLUSION: miR-365a-3p is a novel tissue factor regulator. High E2 concentrations induce a hypercoagulable state via a miR network specific for coagulation factors.

Does the use of hormonal contraceptives affect the mental rotation performance?

Oral contraceptive pill (OC) is one of the most popular form of contraception. Despite both behavioral and neuroimaging evidence of its significant impact on female brain and cognitive functions, much remains to be discovered regarding OCs targets in the brain and mechanisms of action. In the present study mental rotation performance was compared between women using anti-androgenic oral contraceptives (n = 35), naturally cycling (NC) women (n = 33) and men (n = 29). On average, OC users were less accurate than NC women and men. Men performed the task more accurately than NC women, but the difference reached significance only in the highest angular disparity condition (150 deg). The response time was positively related with progesterone level while accuracy was negatively related with 17ß-estradiol level, in NC, but not OC women. The comparison of slope and intercept values (parameters relating response time to angular disparity) revealed the main result of present study: OC users exhibited significantly lower slope compared to men and NC women, but there were no differences in intercept between groups. These results suggest that OC users instead of using rotation in mind strategy implemented some alternative method(s). We conclude that lower performance accuracy of OC users could be related to a less efficient performance strategy.

Treating migraine with contraceptives.

At least 18% of women suffers from migraine. Clinically, there are two main forms of migraine: migraine with aura (MA) and migraine without aura (MO) and more than 50% of MO is strongly correlated to the menstrual cycle. The high prevalence of migraine in females, its correlation with the menstrual cycle and with the use of combined hormonal contraceptives (CHCs) suggest that the estrogen drop is implicated in the pathogenesis of the attacks. Although CHCs may trigger or worsen migraine, their correct use may even prevent or reduce some forms of migraine, like estrogen withdrawal headache. Evidence suggested that stable estrogen levels have a positive effect, minimising or eliminating the estrogenic drop. Several contraceptive strategies may act in this way: extended-cycle CHCs, CHCs with shortened hormone-free interval (HFI), progestogen-only contraceptives, CHCs containing new generation estrogens and estrogen supplementation during the HFI.

Interleukin-6 and Hepcidin Levels during Hormone-Deplete and Hormone-Replete Phases of an Oral Contraceptive Cycle: A Pilot Study.

BACKGROUND: In the past, elevated estradiol levels were reported to downregulate the iron regulatory hormone hepcidin, thereby potentially improving iron metabolism. As estrogen plays a role in regulating the menstrual cycle and can influence the cytokine interleukin-6 (IL-6; a hepcidin up-regulator), this investigation examined the effects of estradiol supplementation achieved by the use of a monophasic oral contraceptive pill (OCP) on IL-6, hepcidin levels and iron status during the hormone-deplete versus hormone-replete phases within an oral contraceptive cycle (OCC). METHODS: Fifteen healthy female OCP users were recruited and provided a venous blood sample on 2 separate mornings during a 28-day period. These included (a) days 2-4 of the OCC, representing a hormone-free withdrawal period (WD); (b) days 12-14 of the OCC, representing the end of the first week of active hormone therapy (AHT). RESULTS: IL-6 and hepcidin levels were not significantly different at WD and AHT. Serum ferritin was significantly higher (p = 0.039) during AHT as compared to WD. CONCLUSIONS: Fluctuations in OCP hormones (estradiol and/or progestogen) had no effect on basal IL-6 and hepcidin levels in young women. Nevertheless, elevated ferritin levels recorded during AHT may indicate that OCP hormones can positively influence iron stores within an OCC despite unchanged hepcidin levels.

The sexuological impact of hormonal contraceptives based on their route of administration.

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E2), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women.

OBJECTIVE: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). METHODS: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18-40 years. In period 1, a single oral dose of an OC containing 30 µg ethinyl estradiol (EE)/150 µg levonorgestrel (LNG) was administered alone. In period 2, the OC was administered with a clinically relevant multiple dose of mavoglurant 100 mg b.i.d. under steady-state conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration, and the PK parameters Cmax and AUClast were estimated using noncompartmental methods. RESULTS: The geometric mean ratios of EE Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval (CI): 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63-0.73), respectively. CONCLUSIONS: In conclusion, EE PK was unchanged, whereas Cmax and AUClast of LNG were 19% and 32% lower, respectively, when given with mavoglurant Further investigation regarding the impact on contraceptive efficacy is warranted.

Hormonal contraceptives, menstrual cycle and brain response to faces.

Both behavioral and neuroimaging evidence support a female advantage in the perception of human faces. Here we explored the possibility that this relationship may be partially mediated by female sex hormones by investigating the relationship between the brain's response to faces and the use of oral contraceptives, as well as the phase of the menstrual cycle. First, functional magnetic resonance images were acquired in 20 young women [10 freely cycling and 10 taking oral contraception (OC)] during two phases of their cycle: mid-cycle and menstruation. We found stronger neural responses to faces in the right fusiform face area (FFA) in women taking oral contraceptives (vs freely cycling women) and during mid-cycle (vs menstruation) in both groups. Mean blood oxygenation level-dependent response in both left and right FFA increased as function of the duration of OC use. Next, this relationship between the use of OC and FFA response was replicated in an independent sample of 110 adolescent girls. Finally in a parallel behavioral study carried out in another sample of women, we found no evidence of differences in the pattern of eye movements while viewing faces between freely cycling women vs those taking oral contraceptives. The imaging findings might indicate enhanced processing of social cues in women taking OC and women during mid-cycle.

Pharmacokinetic drug interactions involving vortioxetine (Lu AA21004), a multimodal antidepressant.

BACKGROUND AND OBJECTIVE: The identification and quantification of potential drug-drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor). METHODS: The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration-time curve [AUC] and maximum plasma concentration [C max]) was used to assess pharmacokinetic interactions. RESULTS: Co-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5'-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80-125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity. CONCLUSION: Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.

Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers.

BACKGROUND: Empagliflozin is a potent, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of patients with type 2 diabetes mellitus. Oral contraceptives may be co-administered with antidiabetic agents over long periods of time, therefore potential drug-drug interactions between oral contraceptives and antidiabetic drugs should be investigated. OBJECTIVE: The effect of multiple oral doses of empagliflozin 25 mg once daily (qd) on the steady-state pharmacokinetics of the combined oral contraceptive ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg qd was investigated. STUDY DESIGN: This was a phase I, open-label, two-period, fixed sequence study. SETTING: The study was performed at the Human Pharmacology Centre/Department of Translational Medicine, Boehringer Ingelheim, Biberach, Germany. PARTICIPANTS: Eighteen healthy premenopausal women participated in the study. INTERVENTION: There was a mandatory run-in period in which participants received EE 30 µg/LNG 150 µg qd for 21-48 days followed by a treatment-free interval of 7 days. Participants then received EE 30 µg/LNG 150 µg qd for 14 days (reference; period 1), followed by EE 30 µg/LNG 150 µg qd plus empagliflozin 25 mg qd for 7 days (test; period 2). MAIN OUTCOME MEASURES: The pharmacokinetics of EE and LNG at steady state based on the primary endpoints of area under the steady-state plasma concentration-time curve during a dosage interval τ (AUC(τ,ss)) and maximum steady-state plasma concentration during a dosage interval (C (max,ss)) were the main outcome measures. RESULTS: The pharmacokinetics of EE and LNG were not affected by co-administration with empagliflozin. Geometric mean ratios (90 % CI) of AUC(τ,ss) and C (max,ss) for EE were 102.82 % (97.58, 108.35) and 99.22 % (93.40, 105.39), respectively. For LNG, these values were 101.94 % (98.54, 105.47) and 105.81 % (99.47, 112.55), respectively. The 90 % CIs were within the standard bioequivalence boundaries of 80-125 %. There were no relevant changes in the time to reach peak levels (t (max,ss)) or terminal elimination half-life (t (½,ss)) of EE and LNG between test and reference treatments. Ten women in each treatment had at least one adverse event (AE). Severe AEs were reported by three women in the reference period and one woman in the test period. There were no serious AEs or premature discontinuations. CONCLUSION: The combination of EE 30 µg/LNG 150 µg and empagliflozin 25 mg was well tolerated. Based on standard bioequivalence criteria, empagliflozin had no effect on the pharmacokinetics of EE and LNG, indicating that no dose adjustment of EE 30 µg/LNG 150 µg is required when empagliflozin is co-administered.

[The effect of oral contraceptives on selected parameters of homeostasis in young women with sudden balance disorders]. / Wplyw dzialania doustnych srodków antykoncepcyjnych na wybrane parametry ukladu hemostazy u mlodych kobiet z naglym zaburzeniem czynnosci ukladu równowagi.

INTRODUCTION: The aim of the study was to evaluate the correlation between hormonal contraceptives and sex hormones levels as a possible cause of vertigo related to coagulation disorders and fibrinolyse. MATERIAL AND METHODS: The study was conducted on 25 female patients aged 23-39, who were treated at the Department of Otolaryngology and Laryngological Oncology, Medical University of Lodz, due to vertigo. The studied patients were divided into 3 groups: I--7 women that used hormonal contraceptives; II--9 women that no used hormonal contraceptives for the last 6 months; III--9 women who never used contraceptives. The methodology included: an otoneurological and audiological examination, blood tests, levels of fibrinogen, D-dimers, APTT, PT, ALAT, ASPAT and BMI, estradiol and progesterone levels. RESULTS: In 16 out of the 25 patients the obtained results diverged from normal sex hormones concentration in serum. In each studied group the relation between sex hormones concentration in serum and coagulation and fibrinolyse parameters was proved. The correlation between an increased concentration progesterone and D-dimers was found. CONCLUSIONS: An increased concentration of estrogens in serum may have an additional negative effect on a possibility of a thromboembolic episode. In the female patients interested in oral contraception, the prophylactic exclusion of risk factors for a thromboembolic disease seems to be vital.

Comparison of serum and cervical mucus hormone levels during hormone-free interval of 24/4 vs. 21/7 combined oral contraceptives.

BACKGROUND: This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens. STUDY DESIGN: This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI. RESULTS: From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone-free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p<.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01). CONCLUSION: This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure.

Combined hormonal contraceptives: is it time to reassess their role in migraine?

OBJECTIVE: This paper will review the extensive array of hormonal contraceptives. It will examine the benefits and risks associated with them - particularly with regard to stroke risk - and shed light on divergent findings in the literature. BACKGROUND: Menstrual-related migraine is a particularly disabling presentation of migraine often deserving of specific prevention. There is accumulating evidence that hormonal preventives may offer such protection. Although a legacy of research shows an increased risk of stroke with high-dose oral contraceptives (OCs) (those containing 50-150µg of estrogen), there is evidence to suggest that this does not apply to ultralow-dose OCs - those containing <25µg ethinyl estradiol - when used in appropriate populations (ie, normotensive non-smokers). Migraine with aura (MwA) increases stroke risk, and that risk is directly correlated to the frequency of aura, a factor that can be modified - either upward or downward - by combined hormonal contraceptives (CHCs). The argument against using CHCs in MwA is based on the concerns that (1) OCs increase stroke risk, (2) MwA increases stroke risk, and (3) combining these risk factors might produce additive or synergistic risk. Evidence does not support concerns (1) and (3), and suggests otherwise. SUMMARY: The risk/benefit analysis of CHCs is shifting. There is growing evidence for a potential role for CHCs in the prevention of menstrual-related migraine. At the same time, the risk of these products is declining, as newer and lower dose formulations replace their historical predecessors. And although migraine aura is a risk factor for stroke, there is not convincing evidence to suggest that the addition of a low-dose CHC alters that risk in non-smoking, normotensive users. Selected hormonal preventives could potentially decrease stroke risk in MwA via reduction in aura frequency achieved by reducing peak estrogen exposure. With this shift in risk/benefit analysis, it is time to reconsider the role of CHCs in migraine - both with and without aura.

Lifetime hormonal factors may predict late-life depression in women.

BACKGROUND: Fluctuating hormone levels are known to influence a woman's mood and well-being. This study aimed to determine whether lifetime hormonal markers are associated with late-life depression symptoms among elderly community-dwelling women. METHOD: Detailed reproductive histories of 1013 women aged 65 years and over were obtained using questionnaires, and depressive symptoms were assessed using the Centre for Epidemiological Studies Depression Scale. Multivariate logistic regression models were generated to determine whether any lifetime endogenous or exogenous hormonal factors were associated with late-life depression. RESULTS: The prevalence of depressive symptoms was 17%. Age at menopause was associated with depressive symptoms, but only among women with a lower education level. For these women, an earlier age at menopause increased their risk of late-life depression (linear effect, OR = 0.95, 95%CI: 0.91-0.99). The odds of late-life depression were also increased for women who were past (OR = 1.6, 95%CI: 1.1-2.5), but were not current users. On the other hand, long-term oral contraceptive use (> or =10 years) was protective against depression (OR = 0.3, 95%CI: 0.1-0.9). These associations remained significant even after extensive adjustment for a range of potential confounding factors, including sociodemographic factors, mental and physical incapacities, antidepressant use and past depression. The other factors examined - including age at first menses, parity, age at childbirth and surgical menopause - were not associated with late-life depressive symptoms. CONCLUSIONS: Lifetime hormonal factors that are significantly associated with depression symptoms in later life have been identified. Further work is needed to determine how potential hormonal interventions could be used in the treatment of late-life depression in certain subgroups of women.

The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study.

OBJECTIVE: To determine whether there are any differences in the incidence of ovarian hyperstimulation syndrome (OHSS) and implantation rates in high-risk patients undergoing IVF using a protocol consisting of GnRH agonist trigger after cotreatment with GnRH antagonist or hCG trigger after dual pituitary suppression protocol. DESIGN: Prospective randomized controlled trial. SETTING: University-based tertiary fertility center. PATIENT(S): Sixty-six patients under 40 years of age with polycystic ovarian syndrome, polycystic ovarian morphology, or previous high response undergoing IVF. INTERVENTION(S): Patients were randomized to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist (study group) or hCG trigger after dual pituitary suppression with a GnRH agonist (control group). Both groups received luteal phase and early pregnancy supplementation with IM progesterone (P), and patients in the study group also received E(2) patches and their doses were adjusted according to the serum levels. MAIN OUTCOME MEASURE(S): Incidence of OHSS and implantation rate. RESULT(S): None of the patients in the study group developed any form of OHSS compared with 31% (10/32) of the patients in the control group. There were no significant differences in the implantation (22/61 [36.0%] vs. 20/64 [31.0%]), clinical pregnancy (17/30 [56.7%] vs. 15/29 [51.7%]), and ongoing pregnancy rates (16/30 [53.3%] vs. 14/29 [48.3%]) between the study and control groups, respectively. CONCLUSION(S): The use of a protocol consisting of GnRH agonist trigger after GnRH antagonist cotreatment combined with adequate luteal phase and early pregnancy E(2) and P supplementation reduces the risk of OHSS in high-risk patients undergoing IVF without affecting implantation rate.

Insulin-like growth factor-1 genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating insulin-like growth factor-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families.

BACKGROUND: BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low penetrance genes that may also modify the risk in BRCA1/2 mutation carriers. The absence of the IGF1 19-CA repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use in nulliparous women of four different ethnic groups. High IGF-1 levels are linked to an increased risk of early-onset breast cancer and to larger breast volumes in the general population. It has also been hypothesized that women whose breast size increases while exposed to OCs may be at increased risk of future breast cancer. AIM: We explored the effect of the IGF1 genotype, specifically the absence of the common 19-CA repeat allele in the promoter region of the IGF1 gene, in combination with oral contraceptive (OC) use or parity on breast volume and IGF-1 levels. MATERIALS AND METHODS: Two hundred fifty-eight healthy women,

Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families.

BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low-penetrance genes, which may also modify the risk in BRCA mutation carriers. The absence of the IGF1 19-repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use. High IGF-1 levels are linked to early-onset breast cancer and larger breast volumes in the general population. The goal of this study was to elucidate the relationships between IGF1 genotype, early-onset breast cancer, breast volume, circulating IGF-1 levels and OC use in a prospective cohort of 258 healthy women < or =40 years old from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured the height, weight, breast volumes and plasma IGF-1 levels. IGF-1 levels were similar among parous and nulliparous women not using OCs. In all, 13% had no IGF1 19-repeat allele. There was an interaction between IGF1 genotype and OC use on IGF-1 levels (P=0.026) in nulliparous women and another interaction between IGF1 genotype and parity on breast volume (P=0.01). Absence of the 19-repeat allele was associated with high IGF-1 levels in nulliparous OC users and with larger breast volumes in parous women and OC users. Incident breast cancers were also more common in women without the 19-repeat allele (log rank P=0.002). Our results suggest that lack of the IGF1 19-repeat allele modifies IGF-1 levels, breast volume and possibly early-onset breast cancer risk after hormone exposure in young high-risk women.

Ischemic colitis during pregnancy and contraceptive medication.

Ischemic bowel disease is generally considered a disease of the elderly and usually consists of reversible colopathy. Nonocclusive causes of ischemic colitis include low-flow states due to cardiac dysfunction and hypovolemia and use of certain medications including progestational medication. We report 2 cases of ischemic colitis in young women. The first one occurred in a young patient who developed three consecutive episodes of ischemic colitis during her pregnancy, whereas the second woman presented with ischemic colitis in relation with the estrogen use. Each episode had a favorable outcome. Having ruled out an infectious cause, or a low blood flow state and in the absence of known thrombogenic disease, we hypothesized the etiology of these ischemic episodes to a high level of circulating estrogens due to pregnancy in the first case and oral contraceptive medication in the second. Physicians treating hemorrhagic colitis in young women should consider the use of contraceptive medication containing estrogens or pregnancy as possible causes.

The effect of olestra on systemic levels of oral contraceptives.

The effect of olestra, a nonabsorbable, noncaloric fat replacement, on the absorption and efficacy of a highly lipophilic oral contraceptive was investigated in a double-blind, placebo-controlled crossover study with 28 women. Subjects consumed 18 gm/day olestra for 28 days while taking an oral contraceptive containing 300 micrograms of norgestrel and 30 micrograms ethinyl estradiol (Lo/Ovral-28). Blood taken on days 12 to 14 of the treatment cycles was analyzed for ethinyl estradiol and norgestrel. There was no statistically significant difference in time to attain maximum concentration, maximum concentration, or area under the concentration-time curve between the olestra and placebo treatments for either drug component. Measurements of serum progesterone indicated that olestra ingestion did not reduce efficacy as indicated by ovulation. The data show that ingestion of 18 gm/day olestra did not affect the absorption or efficacy of the highly lipophilic oral contraceptive.

Role of plasma lipoproteins in the pathogenesis of atherosclerotic disease, with special reference to sex hormone effects.

Plasma lipoproteins constitute a complex lipid transport system. Very low-density lipoproteins transport triglycerides to peripheral tissues, whereas low-density lipoproteins are the main carriers of cholesterol. Cholesterol transport in low-density lipoprotein enters body cells by way of "low-density lipoprotein receptor pathway" but may also be taken up by macrophages by way of the "scavenger pathway." Excessive influx of cholesterol by way of the "scavenger pathway" may result in deposition of cholesterol in arterial walls and atheroma formation. In a yet incompletely known process of "reverse cholesterol transport," cholesterol is carried away from the tissues to the liver by high-density lipoproteins. The above-mentioned transport processes are regulated by a well-synchronized system that involves several enzymes and lipid transport proteins. Under normal conditions, the lipoprotein system is able to balance the flow of cholesterol and other lipids in both directions between the liver and peripheral tissues. This delicate balance may be disturbed by many factors, including contraceptive steroids. The metabolic steps influenced by administration of contraceptive steroids are summarized.

The effects of ampicillin on oral contraceptive steroids in women.

1 Thirteen women taking long term oral contraceptive steroids were studied while taking ampicillin (500 mg three times daily) and compared to a control cycle while not taking ampicillin. 2 There were no significant changes in the plasma concentrations of ethinyloestradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyloestradiol were noted in two women. 3 We conclude that most patients taking oral contraceptive steroids do not need to take alternative contraceptive precautions while taking ampicillin.

PIP: The authors report on a study of women taking oral contraceptives (OCs) to examine the effect of coadministration of the antibiotic ampicillin and to study the mechanism of interaction seen. 7 women between the ages of 19-27 were studied; all were on long-term OC therapy (5 with Eugynon 30, 1 with Ovranette, and 1 with Minovlar). 500 mg 3 times daily for 8 days was prescribed when 4 patients presented with cystitis and 3 patients with acute bronchitis. 6 volunteers between ages 21-24 who had been on long-term OC therapy for at least 3 months (5 with Eugynon 30 and 1 with Ovran) were studied. An identical dose regimen was provided for this group as well. Blood samples were centrifuged for 10 minutes at 2000 rev/minute. Plasma concentrations of ethinyl estradiol (EE), progesterone, FSH, and Ng were measured. Ampicillin concentrations in plasma were measured by a standard microbiological cup plate assay. No subjects displayed any side effects nor was there any evidence of disturbance in cycle control. Among the patients, the mean EE concentration was 46.4 +or- 15.2 pg/ml during ampicillin therapy and 60.2 +or- 4.8 pg/ml after ampicillin, a difference which is not statistically significant. Plasma levonorgestrel concentration was 2.0 +or- 0.3 ng/ml during ampicillin treatment and 2.05 +or- 0.4 ng/ml after (P0.05). FSH concentration during ampicillin was 2.1 +or- 0.3 mIU/ml and 2.05 +or- 0.5 mIU/ml (P0.05) after. Plasma progesterone concentrations did not exceed 200 pg/ml. Ampicillin concentration was not detectable in 4 of the patients. Among the volunteers, the mean plasma EE concentration was 31.4 +or- 5.0 pg/ml before ampicillin while it was 28.2 +or- 2.8 pg/ml during ampicillin therapy. Mean plasma levonorgestrel was 2.13 +or- 0.63 ng/ml before ampicillin and 2.00 +or- 0.59 ng/ml during ampicillin treatment. FSH concentration before ampicillin treatment was 1.12 +or- 0.23 mIU/ml while during ampicillin treatment, the figure was 0.93 +or- 0.27 mIU/ml. In this study, ampicillin had no significant effect on plasma concentrations of EE and levonorgestrel in women taking OCs. 2 recent studies have shown that ampicillin does not significantly interfere with OC therapy. It did not lower plasma OC concentrations and based on this, women taking OCs do not require alternative contraceptive precautions when taking ampicillin.