The impact of reproductive life on breast cancer risk in women with family history or BRCA mutation.

Reproductive history and exogenous hormonal exposures are acknowledged risk factors for breast cancer in the general population. In women at increased breast cancer risk for genetic predisposition or positive family history, data regarding these risk factors are limited or conflicting, and recommendations for these categories are unclear. We evaluated the characteristics of reproductive life in 2522 women at increased genetic or familial breast cancer risk attending our Family Cancer Center. Breast cancers in BRCA mutation carriers were more likely to be hormone receptor negative, diagnosed at 35 years or before and multiple during the lifetime than tumors in women at increased familial risk, while the distribution of invasive cancers and HER2 positive tumors was similar in the different risk groups. At least one full-term pregnancy (HR 0.27; 95% CI 0.12-0.58; p = 0.001), breastfeeding either less (HR 0.24; 95% CI 0.09-0.66; p = 0.005) or more (HR 0.25; 95% IC 0.08-0.82; p = 0.022) than one year and late age at menopause (HR 0.10; 95% CI 0.01-0.82; p = 0.033) showed to be protective factors in BRCA mutation carriers, while in women at increased familial risk early age at first full-term pregnancy (HR 0.62; 95% IC 0.38-0.99; p = 0.048) and late menarche (HR 0.61; 95% CI 0.42-0.85; p = 0.004) showed to be the main protective factors. Finally, for the entire population, combined hormonal contraceptives demonstrated to do not increase breast cancer risk. The results of our study suggest that women at high familial risk and mutation carries develop tumors with different clinical-pathological characteristics and, consequently, are influenced by different protective and risk factors.

What role for Qlaira in contraception?

Around 25% of women in the UK aged 16-49 years use oral contraception.1 Annually, around 5 million combined oral contraceptive (COC) items are prescribed in primary care in England alone, at a cost of over pound40 million. The effectiveness of such contraception depends on correct and consistent use of the pills and is influenced by unwanted effects that can lead to discontinuation (e.g. bleeding irregularities), and by adherence to specified procedures for when a pill is missed. Qlaira (Bayer plc) is the first licensed COC in the UK to include the oestrogen estradiol valerate (E2V, which is metabolised to oestradiol, a natural human hormone) and the progestogen dienogest (DNG). It has been marketed as "the first and only COC to deliver...the same oestrogen as produced by a woman's body". In theory, it might be less likely than other COCs to cause unwanted effects. However, it has a complex dosage regimen, and has its own missed-pill guidance which differs substantially from that for other pills.3 Here we review the effectiveness and place of Qlaira.

Efficacy and safety of a 28-day oral contraceptive with 7 days of low-dose estrogen in place of placebo.

BACKGROUND: The study was conducted to evaluate the efficacy and safety for the prevention of pregnancy of a 28-day oral contraceptive (OC) containing 150 mcg desogestrel (DSG)/20 mcg ethinyl estradiol (EE) for 21 days followed by 7 days of 10 mcg EE (Cette-28). STUDY DESIGN: A 6-month, prospective, multicenter, single-arm study was conducted in 1302 women aged 18-45 years. RESULTS: Over six cycles of treatment, the cumulative risk of pregnancy among all treated subjects (n=1262) was 0.9%. The Pearl Index for women 18-35 years of age (n=1042) was 2.20, including 9 pregnancies with estimated conception dates during active drug ingestion or up to 7 days after the last combination tablet. The rate of unscheduled bleeding was low and the duration of scheduled bleeding was approximately 2 days during each of the six treatment cycles. The safety profile was similar to what has been reported for other OCs. CONCLUSION: This low-dose, 28-day OC incorporating 7 days of 10 mcg EE during the hormone free interval is effective and safe for the prevention of pregnancy and is well-tolerated by women.

The use of triphasic oral contraceptives in a continuous use regimen.

OBJECTIVE: The objective of this study was to describe the characteristics of and outcomes and side effects in patients using triphasic oral contraceptives (OCs) in a continuous use regimen. METHODS: A retrospective review of patient charts from four community-based physician practices was conducted. All patients had been using triphasic OCs in a continuous regimen (i.e., to prevent withdrawal bleeding) for a planned duration of at least three 28-day cycles. Data collected through retrospective chart abstraction included demographic and clinical indicators, duration of and reason for continuous triphasic OC use, prior OC history and side effect incidence and treatment. RESULTS: Forty-three patients meeting the inclusion criteria had data of sufficient quality to be included in all analyses. These patients represented 603 total cycles. Nearly half of the patients (49%) indicated that their primary reason for continuous OC use was personal preference rather than medical reasons. More than half of the patients (56%) had previously used triphasic OCs in a noncontinuous regimen; 24% had no prior OC experience. The median duration of continuous use was 237 days (including right-censored patients; range, 55-994). Of the 39% of patients who terminated continuous use, the most common reason given was the desire to become pregnant (35%). Sixty-one percent of the patients reported no side effects from continuous use. The most common side effect occurring beyond Day 21 of continuous use was breakthrough bleeding (reported in four patients). Survival analysis indicated that time on continuous triphasic use was positively related to parity >0 (p<.05) and the absence of side effects (p<.1). CONCLUSION: The data suggest that successful continuous use is feasible with triphasic OCs, with few adverse side effects.

Upper-extremity deep venous thrombosis complicating whole-blood donation.

BACKGROUND: Up to 36 percent of blood donors may experience a donation-related complication. Fatigue, bruises, hematomas, and vasovagal reactions comprise the great majority of donor reactions and injuries. Serious complications are rare. CASE REPORT: A 20-year-old female taking the third-generation oral contraceptive desogestrel/ethinyl estradiol and ethinyl estradiol (Mircette) developed bruising and increased pain and swelling of her right arm over a 5-day period after whole-blood donation. She was a first-time donor and the venipuncture was reported as being mildly traumatic. There was no personal or family history of thrombosis. RESULTS: Ultrasound examination of her upper extremity revealed the presence of a deep venous thrombosis that required treatment with enoxaparin sodium for 5 days and warfarin for 6 months. Evaluation for thrombophilia was negative. The only risk factor for thrombosis was use of oral contraceptives. CONCLUSION: Although serious complications from whole-blood donation are rare, they may occur. Deep venous thrombosis should be considered in a donor presenting with increasing pain and swelling after blood donation.

Oral contraceptives and libido in women.

Oral contraceptives (OCs) provide safe, effective, and reversible contraception and are widely used by women for fertility control. Little is known about the effects of OCs on sexual functioning. This paper critically examines the published literature addressing the impact of OCs on sexual desire or libido. We reviewed 30 original research studies. In the retrospective, uncontrolled studies (n = 17), it was found that most women reported an increase in libido during OC use. In the uncontrolled, prospective studies (n = 4), it was found that most women reported little change in libido during OC use. In the prospective and cross-sectional controlled studies (n = 4), women using OCs reported both increased and decreased libido compared to non-OC users. The findings from randomized, placebo-controlled studies (n = 5) were mixed: In the most recent and well-conducted trial, a decrease in libido in OC users compared to placebo users was found. Overall, women experience positive effects, negative effects, as well as no effect on libido during OC use. Better-designed studies are needed to establish the independent, causal effects of OCs on libido.

Patient acceptability and satisfaction with Lunelle monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension).

The results from a User Satisfaction Questionnaire, Treatment Assessment Questionnaire, and Global Well-Being Schedule questionnaire administered to women participating in an open-labeled, nonrandomized, parallel, controlled study comparing a new monthly injectable contraceptive containing 25 mg of medroxyprogesterone acetate (MPA) and 5 mg of estradiol cypionate (E2C) (MPA/E2C) (Lunelle Monthly Contraceptive Injection) and a triphasic norethindrone (0.5, 0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive (Ortho-Novum 7/7/7) are reviewed. Approximately 85% of all 1103 women enrolled in the comparative trial completed their initial and final questionnaires. To better assess the comparison of a new and extant method of contraception, outcome data were divided among MPA/E2C users and new and previous oral contraceptive (OC) users. Despite the inherent inequalities in comparing an injectable to an oral method of contraception, few treatment assessment and satisfaction outcomes were significantly different when comparing MPA/E2C users to new OC (NET/EE) users. More women in the MPA/E2C study group reported discomfort with their method than women in either NET/EE study group; however, only 19.4% of MPA/E2C users rated the administration of their contraceptive to be moderately uncomfortable or worse, compared to 11.7% of new NET/EE users and 13.4% of previous OC users. Among MPA/E2C users, 86.3% reported no interference with social activities compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also similar in their responses recommending their respective contraceptive method to friends, with > 90% of both groups stating that they had a very favorable experience and would definitely recommend their method to a friend. In general, MPA/E2C was well accepted by women in the study group. Their attitudes and perceptions are similar to those of women who were starting OCs for the first time. These data support the premise that MPA/E2C may become a well accepted, first-line contraceptive option for women in the US.

PIP: The results of a user satisfaction questionnaire, treatment assessment questionnaire, and global well being schedule questionnaire administered to women participating in an open-labeled, nonrandomized, parallel, controlled study is reported in this paper. The study compared a new monthly injectable contraceptive containing 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate (E2C) with a triphasic norethindrone (0.5, 0.75, 1.0 mg)/0.035 mg ethinyl estradiol (NET/EE) oral contraceptive. Approximately 85% of 1103 women enrolled in the comparative trial completed their initial and final questionnaires. Despite the inherent inequalities in comparing an injectable to oral contraception, few treatment assessment and satisfaction outcomes were significantly different when comparing MPA/E2C users to new NET/EE users. More women in the MPA/E2C group reported discomfort with their method compared to the women in either the new or previous NET/EE user group. However, only 19.4% of MPA/E2C users rated the administration of their contraceptive to be moderately uncomfortable or worse, compared to 11.7% of new NET/EE users and 13.4% of previous NET/EE users. Among MPA/E2C users, 86.3% reported no interference with social activities compared with 90.4% of new NET/EE users. MPA/E2C and new NET/EE users were also similar in their responses recommending their respective contraceptive method to friends. These data support the premise that MPA/E2C may become the well-accepted, first-line contraceptive option for women in the US.

[Regression of a focal nodular hyperplasia after stopping oral contraceptives]. / Régression d'une hyperplasie nodulaire focale après arrêt d'une contraception orale.

The complete regression of a focal nodular hyperplasia of the liver with typical MRI patterns 5 years after withdrawal of oral contraceptives was observed. Effects of oral contraceptives on this tumor's evolution and appropriate imaging by MRI are discussed.

A triphasic oral contraceptive pill, CTR-05: clinical efficacy and safety.

OBJECTIVE: The primary objective of this study was to compare the safety, contraceptive efficacy, and menstrual cycle patterns in women using triphasic oral contraceptive pills, namely CTR-05, containing 50/100/150 micrograms desogestrel and 35/30/30 micrograms ethinylestradiol, and Orthonovum777 containing 500/750/1000 micrograms norethindrone and 35/35/35 micrograms ethinylestradiol. METHOD: Forty-six female volunteers, satisfying the selection criteria, were evaluated for six cycles, in an open-label, randomized study. Volunteers using CTR-05 were studied for 13 additional cycles for efficacy and safety. RESULTS: No serious adverse effects were observed in either group. The incidences of other drug-related adverse effects, such as headache and nausea, were transient in both groups. CTR-05 did not lower levels of high density lipoprotein (HDL) cholesterol. This may be attributed to the lower androgenicity of its progestin component, desogestrel. No pregnancies were reported in either group. Clinical and laboratory parameters remained within normal limits in both groups. In the CTR-05 group, the lower dose of ethinylestradiol did not affect the safety, efficacy and acceptability of the product. CONCLUSION: Desogestrel, with little estrogenic activity and only minimal androgenic activity, leads to lipoprotein changes, resulting in a favorable cardiovascular profile, as well as minimal androgen-related effects, such as hirsutism and acne.

[Mesenteric vein thrombosis with hemorrhagic infarct of the small intestinal as a complication of oral contraceptives]. / Mesenterialvenenthrombose mit hämorrhagischem Dünndarminfarkt als Komplikation oraler Contraceptiva.

Venous thrombosis is a documented complication of oral contraceptives in adolescents and young women. The frequency of thrombosis increases in presence of additional risk factors as e.g. smoking and obesity. This is a case-report of a mesenterial vein thrombosis in a 24 years old woman on low estrogen dose triphasic oral contraceptives combined with smoking and obesity. Wide jejunal haemorrhagic infarction with acute abdomen and volume deficiency shock conducted to diagnosis finally by emergency laparotomy. Wide resection of jejune was required.

Use of levonorgestrel implants versus oral contraceptives in adolescence: a case-control study.

OBJECTIVE: We compared continuation rates, effectiveness, satisfaction with method, side effects, and condom practices among adolescents using levonorgestrel implants (Norplant, Wyeth-Ayerst Laboratories, Philadelphia) as compared with oral contraceptives. STUDY DESIGN: We conducted a case-control study comparing 94 adolescents < or = 18 years old who received Norplant between March 1, 1992, and Nov. 1, 1993 (cases), with 94 age-matched controls who selected oral contraceptives during this same time period. By use of a structured questionnaire, information was obtained on pregnancy status, duration of use, patient satisfaction, side effects, and condom practices 6 months after initiation. Objective measures included weight on Norplant and oral contraceptive users and hematocrit on implant patients. RESULTS: Forty (43%) oral contraceptive patients compared with no Norplant patients discontinued their selected method before the 6-month interview (p = 0.00). Six patients prescribed oral contraceptives became pregnant. Ninety-three percent of Norplant users expressed overall satisfaction despite experiencing menstrual irregularity and cramping, amenorrhea, nervousness, abnormal hair growth or loss, rashes, and an increase in appetite more often than oral contraceptive users. Although Norplant patients also reported an increase in the duration of menstrual flow and number of days of spotting more often than oral contraceptive users, evaluation of hematocrits in these patients demonstrated a significant increase over the 6-month period (p = 0.00). Assessment of condom practices since initiation demonstrated that Norplant patients used condoms less often than oral contraceptive users (p = 0.00). CONCLUSION: Use of levonorgestrel implants may cause more side effects than oral contraceptives in the early months after initiation but provide superior protection against unintended pregnancy. We concluded that Norplant is a reasonable alternative for adolescents, especially when compliance is an issue.

Advances in oral hormonal contraception.

PIP: Researchers continue to search for newer oral contraceptive (OC) formulations that retain the pill's beneficial effects while minimizing side effects. Changes in the clinical profile of OCs since their introduction in 1960 have enhanced their safety and acceptability. Most notable has been a trend toward the reduction of the pill's estrogen dose to 15-20 mcg of ethinyl estradiol and the consequent decline in cardiovascular risks attributable to thromboembolic processes. In addition, research has been directed toward the identification of selective gonane progestins that do not have the same atherogenetic impact as their predecessors. The low-dose gonane progestins may provide protection against cardiovascular disease through their beneficial impact on lipid profile. New regimes currently under study include a 23-24-day/month use pattern to reduce follicular ripening, use of estradiol rather than ethinyl estradiol, and the identification of progestins with special anti-androgenic effects. Also under investigation is the contraceptive potential of antiprogestogens such as RU-486. At present, the non-contraceptive benefits of OC use include reductions in ovarian and endometrial cancer, fewer ovarian cysts, less benign breast disease, a lower incidence of pelvic inflammatory disease, and less menorrhagia.^ieng

The relationship between mood and sexuality in women using an oral contraceptive as a treatment for premenstrual symptoms.

This study investigated the effects of a triphasic oral contraceptive (OC) on mood and on sexual interest in a group of 45 women with premenstrual complaints. Subjects made daily ratings of mood and sexual interest for one baseline cycle and were then randomly assigned to receive either placebo or OC for 3 mo. Women who received the OC reported decreased sexual interest during the menstrual and postmenstrual phases of the cycle. The predominant effect of both the OC and the placebo on mood was one of improvement, particularly during the premenstrual phase. There was little evidence of co-variation of mood and sexual interest in either group. Although the mechanism for the adverse effects of the OC on levels of sexual interest in unknown, it is clear that this effect was not simply a consequence of pill-induced negative mood change. The findings provide evidence that mood and sexual desire are dissociable and suggest that OCs can have direct effects on women's sexuality.

PIP: In Montreal, Canada, after 45 women who were seeking treatment for self-reported moderate to severe premenstrual changes made daily ratings of mood and sexual interest for 1 baseline cycle, they were blindly allocated to a group receiving a triphasic oral contraceptive (OC) Synphasic for 3 months or a group receiving a placebo for 3 months. Researchers wanted to determine the effects of the OC on mood and on sexual interest. Ratings of depression and sexual interest in both groups demonstrated significant cyclicity. For example, depression scores were highest during the premenstrual phase and lowest during the postmenstrual phase. Sexual interest peaked in the postmenstrual phase and bottomed out in the premenstrual phase. Both groups experienced a loss of cyclicity for mood and sexual interest by the 3rd treatment cycle. During the premenstrual phase, depression scores fell significantly in both groups (p .01), but an increase in sexual interest did not occur. During the menstrual phase, the OC group experienced a considerable drop in sexual interest (p .01), but the mood did not change. On the other hand, postmenstrually, the mood worsened, not significantly however, among the OC users, coinciding with a significant reduction in sexual interest (p .01). Yet mood and sexual interest were not correlated. In fact, covariation of mood and sexual interest basically did not occur in either group. Generally, both the OC and the placebo improved the mood, especially during the premenstrual phase. The negative effect of the OC on sexual interest was not just a result of OC induced negative mood change. These results show that mood and sexual desire are not linked. They intimate that OCs directly influence women's sexuality.

[Response to the letter by Prof. Kuhl: "Does a rise in endogenous estradiol during treatment with low-dose ovulation inhibitor signify increased risk"?]. / Erwiderung zum Leserbrief von Herrn Prof. Kuhl: "Bedeutet ein Anstieg des endogenen Oestradiols während der Behandlung mit niedrig dosiertem Ovulationshemmer (OH) ein erhöhtes Risiko"?

PIP: During testing new sequential preparations such as Trinordiol the weak suppression of gonadotropin and the partly increased endogenous estradiol (E2) and also partly increased progesterone were noted in the course of 30,000 checkups by contraceptive users when clinical symptoms were confirmed by ultrasound and biochemical analysis. In micropill users these were acute abdominal and breast pain, often follicular ripening in the ovaries, and cysts in the ovaries and in the breast with increased E2 values up to ovulatory values in some. The strong pain in the lower abdomen required intervention. It has been known that ethinyl estradiol (EE) and gestagens inhibit ovulation. In a study of 7 patients taking 40 mcg of gestoden there were 6 cases of ovulation inhibition (4 times along with follicular ripening) and 1 case of corpus luteum insufficiency. There were 2 instances of follicular ripening in 32 patients using Femovan containing 30 mcg of EE with 75 mcg of gestoden. With a 20 mcg preparation these signs occurred repeatedly when young girls complained of strong breast pain and breast enlargement. Shifting to a preparation containing 30 mcg of EE with the same dose of gestagen eliminated the complaints. This contradicts the hypothesis that all receptors are occupied by Ee and that endogenous E2 production cannot exercise its effect. Therefore, development of micropills with a somewhat higher gestagen dose has been suggested. There are patients whose cycle regulation is aided only by sequential preparations with 50 mcg of EE. It is concluded that ovulation inhibition is dependent on the dose and structure of gestagens, with the resorption and current metabolism of steroids in agreement with individually differing suppression of the ovaries.^ieng