Acute pancreatitis secondary to oral contraceptive-induced hypertriglyceridemia: a case report.

Hypertriglyceridemia is the third most common cause of acute pancreatitis. Among the causes that lead to secondary hypertriglyceridemia, the use of contraceptive agents is the main reason to be assessed in young women. We report a case of a 31-year-old woman who had suffered two acute pancreatitis episodes secondary to hypertriglyceridemia. In the investigation, the previous medical team indicated a genetic screening before ruling out all secondary causes. LPL, apo CII and apo AV genes were negative for mutations. In the first appointment with us, the patient reported the use of a contraceptive agent for about 2 years. She was instructed to discontinue the drug. After one year of follow-up, her serum triglycerides are within the normal range and a copper intrauterine device was the method chosen by the patient for contraception.

Body mass index does not affect the efficacy or bleeding profile during use of an ultra-low-dose combined oral contraceptive.

OBJECTIVES: Safe and effective contraceptive options for obese women are becoming more important due to the obesity epidemic within the United States. This study evaluated the impact of body mass index (BMI) on efficacy, safety and bleeding patterns during use of an ultra-low-dose combined oral contraceptive (COC). STUDY DESIGN: Data are from a Phase 3 clinical efficacy and safety study of an ultra-low-dose COC containing 1.0-mg norethindrone acetate and 10-mcg ethinyl estradiol. Pearl Indices, adverse events and bleeding profile were calculated for BMI ranges of <25, 25-30 and >30 kg/m(2). RESULTS: Of the 1581 participants included in the analysis, 28.3% were overweight, and 18.0% were obese. For women aged 18-45 years, the Pearl Indices were 2.49, 2.32 and 1.89 for women with a BMI <25, 25-30 and >30 kg/m(2), respectively. The ultra-low dose of ethinyl estradiol did not impact scheduled bleeding or intensity of bleeding, but we observed a slight decline in amenorrhea and slight increase in unscheduled bleeding in obese women compared with other BMI categories. CONCLUSIONS: Our analysis of an ultra-low-dose COC did not find clinically important differences in contraceptive failure rates, adverse events or bleeding profile with increasing BMI. IMPLICATIONS: Our analysis of an ultra-low ethinyl estradiol dose COC did not find clinically important differences in contraceptive failure rates, adverse events or bleeding profile with increasing BMI. An ultra-low-dose COC provides another safe and effective contraceptive option for obese women.

Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug-drug interactions between depot medroxyprogesterone acetate (DMPA) and twice-daily lopinavir (LPV) plus low-dose ritonavir (RTV) (LPV/r) among 24 HIV-infected women and compared the results to those for HIV-infected women receiving DMPA while on no antiretroviral therapy or on nucleosides only (n = 14 subjects from the control arm of AIDS Clinical Trials Group [ACTG] study 5093). The objectives of the study were to address the effect of LPV/r on DMPA and to address the effect of DMPA on LPV/r therapy. PK parameters were estimated using noncompartmental analysis with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of LPV and RTV PKs before and 4 weeks after DMPA dosing. Plasma progesterone concentrations were measured every 2 weeks after DMPA dosing through week 12. Although the MPA area under the concentration-time curve and maximum concentration of drug in plasma were statistically significantly increased in the study women on LPV/r compared to those in the historical controls, these increases were not considered clinically significant. There were no changes in LPV or RTV exposure after DMPA. DMPA was well tolerated, and suppression of ovulation was maintained. (This study has been registered at ClinicalTrials.gov under registration no. NCT01296152.).

[Cardiovascular risks of combined oral contraceptives - beyond the French controversy]. / Risques cardiovasculaires de la contraception orale estro-progestative : au-delà de la polémique

Combined hormonal contraceptive is the most used contraceptive method in France among childbearing-aged women. Following the temporary delisting of oral contraception containing a 3rd generation progestin and following the market withdrawal of oral pills containing cyproterone acetate in combination with ethynil-estradiol (35µg), the impact of these events on our prescribing practice remains to determine. We will especially discuss the cardiovascular risk associated with combined hormonal contraceptives in the light of the most recent publications either with epidemiological or biological data.

Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study.

OBJECTIVE: To compare the efficacy of two hormonal therapies in treating symptoms caused by bowel endometriosis. DESIGN: Patient preference study. SETTING: University hospital. POPULATION: A total of 143 women with rectovaginal endometriosis infiltrating the rectum. METHODS: This study was performed between January 2008 and June 2011. Patients were treated with a desogestrel-only contraceptive pill or with the sequential combined contraceptive vaginal ring for 12 months. MAIN OUTCOME MEASURES: The primary endpoint of the study was the rate of satisfied patients at 12-month follow up. The changes in symptoms and in the volume of the nodules were secondary endpoints. RESULTS: At 12-month follow up, the rate of satisfied patients was higher in the group treated with the desogestrel-only contraceptive pill than in the group treated with the sequential combined contraceptive vaginal ring (p = 0.004). When only changes in gastrointestinal symptoms were considered, 50% of patients treated with the desogestrel-only contraceptive pill and 31.3% of those treated with the sequential combined contraceptive vaginal ring were satisfied (p = 0.037). The reduction in the volume of the nodules, the percentages of patients who discontinued the therapy after the completion of the study and of those who decided to undergo surgery were similar between the two groups. CONCLUSIONS: Both hormonal therapies are efficacious in treating symptoms caused by rectovaginal endometriosis infiltrating the rectum. Patient satisfaction is higher with the desogestrel-only pill than with a vaginal ring.

Retrospective review of norethindrone use in adolescents.

STUDY OBJECTIVE: Our objectives were to review norethindrone use in an adolescent population in a tertiary care center and to assess the effectiveness of the norethindrone taper in the management of acute heavy menstrual bleeding in adolescents. DESIGN: Retrospective cohort study. SETTING: Tertiary care center. PARTICIPANTS: 176 adolescent females prescribed norethindrone 0.35 mg between July 2007 and September 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Discontinuation and irregular bleeding rates. RESULTS: Mean age was 14.8 ± 2.3 years. Most common indication for use was heavy menstrual bleeding (32.9%). Most common reasons for use of a progestin only pill were neurologic (27.8%) and cardiovascular diseases (17.6%). Discontinuation rate was 48.5%, most commonly for irregular bleeding (54.5%). Irregular bleeding and systemic side effects were associated with discontinuation (P = .006 and .003 respectively). No serious adverse events were reported. Twenty patients required norethindrone taper for heavy bleeding; of this group 78.9% experienced complete cessation of bleeding within 7 days. CONCLUSIONS: Our findings support use of norethindrone as an effective alternative among adolescents with contraindications to administration of estrogen and for whom control of acute heavy menstrual bleeding is desired.

Mifepristone: a potential clinical agent based on its anti-progesterone and anti-glucocorticoid properties.

Nowadays, unwanted pregnancy is a major globe tragedy for millions of women, associated with significant direct and indirect costs, no matter for individuals or society. The progesterone receptor antagonist steroid, mifepristone has been widely and effectively using throughout the world for medical abortion, but to a lesser extent for emergency contraception. In this review, we hope to explore the role of mifepristone as a contraceptive, particularly for emergency contraception. Studies of mifepristone have also been expanding to the fields of endometriosis and uterine fibroids. Furthermore, this initially considered reproductive medicine has been investigated in some psychotic diseases and various disorders of hypercortisolism, because of its glucocorticoid receptor antagonism. Mifepristone was approved suitable for patients with hyperglycemia secondary to Cushing's syndrome by the United States Food and Drug Administration (FDA) in 2012. The aim of this article is to review published reports on the anti-progesterone and anti-glucocorticoid properties of mifepristone as a clinical agent. There is a new insight into systematically describing and evaluating the potential efficiency of mifepristone administrated in the field of endocrine and neuroendocrine, not only in obstetrics and gynecology.

Decidual cast after discontinuation of oral contraceptives use in a young girl.

BACKGROUND: The differential diagnosis of tissue passed per vagina in a young girl includes aborted pregnancy, rhabdomyosarcoma, polyp, and very rarely decidual cast. CASE: A 10-year-old girl using oral contraceptives for menorrhagia presented with a decidual cast after discontinuing the drug. Symptoms disappeared during clinical follow-up without any intervention. CONCLUSIONS: Decidual cast formation is an unusual entity of unknown origin. It's generally seen during treatment with variable contraceptives. This is the first case described with desogestrel and it occurred after discontinuing treatment.

Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome.

OBJECTIVE: To compare the effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone, in polycystic ovary syndrome (PCOS), after 6 and 12 months of therapy. DESIGN: Double-blind randomized controlled trial. SETTING: Gynecologic clinic of the first author. PATIENT(S): Women (n = 171) with PCOS (Androgen Excess Society criteria, 2006). INTERVENTION(S): The three-arm trial involved 58, 56, and 57 cases in desogestrel, cyproterone acetate, and drospirenone groups, respectively. Body mass index, abdominal circumference, hirsutism score (modified Ferriman Galwey), acne and acanthosis nigricans scores, and blood pressure were noted. Blood levels of total T, sex hormone-binding globulin, fasting glucose, and fasting insulin were measured. Free androgen index, glucose-insulin ratio, and homeostasis model assessment-insulin resistance were calculated. Follow-up was after 6 and 12 months of treatment. MAIN OUTCOME MEASURE(S): Primarily, absolute change in the Free Androgen Index score between the three groups and, secondarily, changes in the clinical and other hormonal and biochemical parameters were studied. RESULT(S): Six months of treatment showed similar effects. After 12 months, cyproterone acetate significantly decreased the modified Ferriman Galwey score (change = -5.29) compared with both desogestrel (change = -1.69) and drospirenone (change = -2.12); cyproterone acetate significantly increased sex hormone-binding globulin (change = 142.91) compared with desogestrel (change = 99.53); drospirenone significantly increased sex hormone-binding globulin (change = 131.52) compared with desogestrel; and cyproterone acetate significantly decreased the Free Androgen Index (change = -10.57) compared with desogestrel (change = -5.58). CONCLUSION(S): No difference in effects after 6 months. At 12 months, cyproterone acetate showed the strongest antiandrogen activities. Effects on metabolic parameters were identical. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2010/091/000332.

Progestin-only contraceptive pill use among women in the United States.

BACKGROUND: Progestin-only contraceptive pills (POPs) offer a safe and effective contraceptive option, particularly for women at increased risk of venous thromboembolism. However, the prevalence of POP use among women in the United States is unknown. STUDY DESIGN: We analyzed population-based data from 12,279 women aged 15-44 years in the National Survey of Family Growth. Data were collected continuously from 2006 to 2010 by in-person, computerized household interviews. Analyses describe POP use across sociodemographic and reproductive characteristics and thromboembolic risk profiles. RESULTS: Overall, 0.4% of all reproductive-aged women in the United States currently use POPs. POP use was higher among parous, postpartum and breastfeeding women than their counterparts (all p values<.001). Women at higher risk of thromboembolism (older, obese, diabetic or smoking women) had similar proportions of POP use as women without those risks. CONCLUSION: POPs are rarely used by US women. While data on chronic disease were limited, our results suggest that relatively few women with increased risk of thromboembolism are considering POPs when choosing an oral contraceptive.

Relation of androgen receptor sensitivity and mood to sexual desire in hormonal contraception users.

BACKGROUND: Since very little research in this field is available, this study aims to assess the role of psychosexual, relationship, hormonal and genetic measures in the sexual desire of users of three hormonal contraceptive products [low-dose combined oral contraceptive (20 mcg ethinylestradiol/150 mcg desogestrel), progestin-only pill (75 mcg desogestrel) and vaginal ring (daily dose of 15 mcg ethinylestradiol/120 mcg etonogestrel)]. STUDY DESIGN: Fifty-five couples were randomized over three groups in which the women consecutively used each product during 3 months. Both partners repeatedly filled out questionnaires on solitary and dyadic sexual desire (desire to behave sexually by oneself or towards a partner). Total and free testosterone, sex hormone binding globulin and a genetic marker of androgen receptor sensitivity [cytosine-adenine-guanine (CAG) repeat length] were assessed on blood samples of the female partners. RESULTS: Sexual desire was higher in women with either short or long CAG repeats (solitary, p=.004; dyadic, p=.008). Desire levels were higher during vaginal ring use (solitary, p=.018; dyadic, p=.007). The woman's mood was found to impact her dyadic sexual desire (p<.001); this scale was also strongly associated with the male partner's dyadic sexual desire (p<.001). CONCLUSIONS: The current study found evidence for a role of androgen receptor sensitivity and mood in the sexual desire of hormonal contraceptive users.

Reciprocal coordination of a combination oral contraceptive containing desogestrel+ethinyl estradiol on the expression of LOX-1 and LDLR in placental trophoblast cells.

BACKGROUND: The aim of this study was to assess the consistency of antiatherosclerotic potential of a combination oral contraceptive steroid (ethinyl estradiol+desogestrel) by rating its effect on the differential expression of the low-density lipoprotein receptor (LDLR) and lectin-like oxidized LDL (LOX-1) receptor. STUDY DESIGN: Cells from placental trophoblast cell line (JAR) and differentiated primary placental trophoblast cells isolated from term human placentae were used for this study. Expressions of LOX-1 and LDLR were assessed by immunoblot and immunocytochemistry assays. Differential effects of the constituent steroids in the combination of ethinyl estradiol and desogestrel were verified on the expression profile of the receptors. RESULTS: Desogestrel opposed the effect of ethinyl estradiol on LOX-1 expression, and when used in combination, the combination oral contraceptive reduced the expression of LOX-1 in contrast to LDLR. The characteristic change in the expressions of LOX-1 and LDLR showed an antiatherosclerotic improvisation at the unique combination of ethinyl estradiol (10 ng/mL) and desogestrel (20 ng/mL). CONCLUSION: The aforesaid combination of ethinyl estradiol and desogestrel keeps LOX-1 and LDLR reciprocally expressed in antiatherosclerotic mode.

Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17ß-oestradiol in a 24/4 regimen, in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen.

OBJECTIVES: The primary objective was to assess the efficacy, cycle control and tolerability of a monophasic combined oral contraceptive (COC) containing nomegestrol acetate (NOMAC) and 17ß-oestradiol (E2). Effects on acne were evaluated as a secondary objective. Results were compared to those of a COC containing drospirenone (DRSP) and ethinylestradiol (EE). METHODS: Women (aged 18-50 years) were randomised to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n=1591) or DRSP/EE (3 mg/30 µg) in a 21/7-day regimen (n=535) for 13 cycles. RESULTS: Estimated Pearl Indices for NOMAC/E2 and DRSP/EE were 0.38 and 0.81 in women aged≤35 years and 0.31 and 0.66 for all women (18-50 years), respectively. Scheduled withdrawal bleedings were shorter and lighter among users of NOMAC/E2 and were sometimes absent altogether. Intracyclic bleeding/spotting was infrequent in both groups, and decreased over time. Type and frequency of adverse events were similar to those typically reported for COCs. CONCLUSIONS: These data show that NOMAC/E2 provides high contraceptive efficacy with acceptable cycle control as well as an overall adverse event profile similar to that of DRSP/EE.

Effect of ticagrelor on the pharmacokinetics of ethinyl oestradiol and levonorgestrel in healthy volunteers.

BACKGROUND: Cytochrome P450 3 A is involved in ticagrelor and ethinyl oestradiol/levonorgestrel metabolism; so a potential drug-drug interaction may occur. OBJECTIVES: To assess: ticagrelor effects on ethinyl oestradiol/levonorgestrel pharmacokinetics, endogenous sex hormone levels; ethinyl oestradiol/levonorgestrel effects on ticagrelor pharmacokinetics; tolerability of ticagrelor + ethinyl oestradiol/levonorgestrel. METHODS: This trial was a randomized, double-blind, two-way crossover, single-center study. Twenty-two healthy female volunteers (on stable ethinyl oestradiol/levonorgestrel) received 90 mg ticagrelor or placebo twice daily with ethinyl oestradiol/levonorgestrel (0.03 mg/0.15 mg; Nordette) on cycle days 1-21. Volunteers crossed over treatment on day 1/cycle 2. Pharmacokinetic parameters were evaluated on cycle day 21, and endogenous hormones assayed on cycle days 1, 7, 14 and 21. CLINICAL TRIAL REGISTRATION NUMBER: NCT006895906. RESULTS: Ethinyl oestradiol absorption was rapid (median t(max) approximately 1 hour), and was not affected by ticagrelor. Ticagrelor co-administration (90% confidence interval [CI]) increased AUC(0-τ), C(min), and C(max) of ethinyl oestradiol by 20% (1.03-1.40), 20% (0.96-1.50) and 31% (1.18-1.44), respectively. Ticagrelor had no effect on levonorgestrel pharmacokinetic parameters versus placebo (90% CI: AUC(0-τ) 0.97-1.10; C(min) 0.94-1.10; C(max) 1.02-1.16). Steady-state ticagrelor, and AR-C124910XX (major and equally pharmacologically active metabolite), AUC(0-τ), C(max), and t(max) were comparable with published findings. Pre-dose ticagrelor and AR-C124910XX plasma concentrations were higher on cycle day 21 versus days 7 and 14. Endogenous sex hormone plasma levels were unaffected by ticagrelor. Co-administration of ticagrelor with ethinyl oestradiol/levonorgestrel was well tolerated. Study limitations included: no ticagrelor-only arm; only one type of oral contraceptive; short study duration; using oestradiol/levonorgestrel pharmacokinetic parameters as surrogate marker for contraceptive efficacy. CONCLUSIONS: Ticagrelor co-administration with ethinyl oestradiol/levonorgestrel increased ethinyl oestradiol exposure by approximately 20%, with no effect on levonorgestrel pharmacokinetics. No clinically relevant effect on contraceptive efficacy is expected with ethinyl oestradiol/levonorgestrel and ticagrelor co-administration.

A case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis.

OBJECTIVE: Women have exhibited anaphylaxis, urticaria/angioedema, and autoimmune progesterone dermatitis (APD) coinciding with the progesterone premenstrual rise. We report a detailed immunological evaluation of such a woman responsive to a gonadotropin hormone-releasing agonist (GHRA). METHODS: Skin testing, enzyme-linked immunosorbent assays (ELISAs), leukocyte histamine release (LHR), and inhibition assays were performed to demonstrate progesterone immunoresponsiveness. RESULTS: Serum specific-progesterone immunoglobulin G (IgG) and IgE were detected initially and disappeared 6 months after GHRA treatment. Dose-response LHR using patient basophils was observed for different hormones but after 3 months persisted only for 5ß-pregnanediol. Preincubation with mouse antiprogesterone monoclonal antibody (PmAb) or mifepristone, a progesterone inhibitor, over a range of doses inhibited specific progesterone-induced LHR. Experiments with varying progesterone concentrations and a fixed dose of anti-IgE resulted in 100% LHR at a concentration as low as 0.016 nmol/mL, which, without anti-IgE, failed to release histamine. CONCLUSIONS: This is the first report of combined recurrent anaphylaxis, cyclic urticaria/angioedema, and APD induced by immunoresponsiveness to progesterone.

Nomegestrol acetate, a novel progestogen for oral contraception.

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism. In normal and cancerous human breast tissue, NOMAC has shown favorable effects on estrogen metabolism, and in human breast cancer cell lines in vitro, it does not stimulate cell proliferation. The pharmacologic profile of NOMAC suggested that it would be well suited for combination with a physiologic estrogen in a combined oral contraceptive (COC), with the aim of achieving effective contraception with good cycle control and a favorable safety profile. A monophasic COC containing NOMAC 2.5mg and 17ß-estradiol (E2) 1.5mg, administered in a 24/4-day regimen, is currently under clinical investigation. In a phase III study, NOMAC/E2 provided consistent and robust ovulation inhibition, with contraceptive effects that compared favorably with those of drospirenone 3mg/ethinyl estradiol (EE) 30 µg. Investigators for a second phase III study reported less overall impact with NOMAC/E2 on hemostatic, lipid, inflammatory, and carbohydrate metabolism parameters than with levonorgestrel 150 µg/EE 30 µg. These clinical findings are promising; however, full publication of results from the pivotal phase III trials of NOMAC/E2 is pending.

The use of newer progestins for contraception.

The synthetic progestins used for contraception so far are structurally related either to testosterone (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor (GR) interactions. Dienogest (DNG) and drospirenone (DRSP) exhibit a partial antiandrogenic action, and DRSP has predominant anti-mineralocorticoid properties. The 19-norpregnanes include Nestorone (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG), and possess a high specificity for binding to the progesterone receptor (PR) with no or little interaction with other steroid receptors. DRSP has been developed as combination oral pills with ethinyl estradiol (EE); DNG has been combined both with EE and, more recently, with estradiol valerate (E2V). NOMAc has been used as a progestin-only method and more recently combined with estradiol (E2). Nestorone is not active orally but proved to be the most active antiovulatory progestin when used parenterally. It has been developed in various formulations such as implants, vaginal rings or transdermal gel or spray. Risks and benefits of the new progestins depend upon the type of molecular structure, the type of estrogen associated in a combination and the route of administration.

Endometrial safety of a novel monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4-day regimen over six cycles.

BACKGROUND: This study was conducted to examine whether small doses of ethinylestradiol (EE, 0.02 mg) and chlormadinone acetate (CMA, 2 mg) administered in a novel 24/4-day regimen during six cycles would suffice to suppress proliferation and to cause secretory changes in the endometrium. STUDY DESIGN: This Phase II, randomized (two assessment groups), single-center, open, uncontrolled, multiple-dosing study treated 59 female subjects. The subjects underwent three endometrial biopsies: one pretreatment, one during medication (either at Cycle 3 or Cycle 6) and one during the first post-treatment cycle. RESULTS: The study revealed that 0.02 mg EE/2 mg CMA effectively transformed the endometrium from a proliferative state into a secretory or inactive state after three (90% of subjects) and six (76% of subjects) medication cycles. The mean endometrial thickness decreased markedly from 10.2 (SD±3.0) mm (pretreatment) to an unfavorable level for the nidation of a blastocyst [5.3 (SD±2.1) and 4.1 (SD±2.2) mm in Medication Cycles 3 and 6, respectively]. Correspondingly, estradiol and progesterone levels decreased during treatment. In the post-treatment cycle, endometrial biopsy and ultrasound evaluation as well as sex hormone levels suggested a quick return to fertility. There were no signs of hyperplasia, endometrial polyps, neoplasia or other detrimental histopathological changes at any time during the trial. Treatment-related adverse events (AEs) were reported by 22 (37%) of 59 subjects and were reported most commonly in Cycle 1, decreasing continuously thereafter. No AEs led to discontinuation of the trial medication and there were no serious AEs. CONCLUSIONS: The 24/4-day regimen of 0.02 mg EE/2 mg CMA provided effective and reversible endometrial effects with secretory transformation or suppression without inducing pathological changes.