Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Assessment of acquired activated protein C resistance with the FibWave and comparison with the ETP-based APC resistance.

INTRODUCTION: Activated protein C (APC) resistance is a major risk factor of venous thrombosis which may be acquired by hormonal therapy or other causes. The FibWave, a sensitive global clot-based assay design to analyze the coagulation kinetics in plasma, may be a good candidate to assess this prothrombotic state. This study aims to assess the suitability of the FibWave to differentiate the coagulation kinetics of women on oral contraceptives. MATERIALS AND METHODS: Fifty-four healthy volunteers were divided into 5 groups: men [n = 13], women not using hormonal contraception [n = 12], women using second [n = 12] or third generation [n = 12] combined oral contraceptives, and women using progestin only contraceptive [n = 5]. Patients with coagulation abnormalities were also assessed [n = 8]. The APC resistance was assessed on the FibWave using exogenous APC or Protac, and on the Calibrated Automated Thrombogram using the ETP-based APC resistance assay. RESULTS: Either in presence or in absence of APC or Protac, the FibWave was able to detect a hypercoagulable state in plasma samples. All combined oral contraceptives showed a lower FW-Max1 , FW-Max2, and FW-Min2 percentage of inhibition and a lower FW-Ttpeak ratio than the other groups. The sensitivity of the FibWave was similar to the one of the ETP-based APC resistance assay. CONCLUSION: The FibWave is able to differentiate APC resistance levels observed in women on combined oral contraceptive. The FW-Max1 , FW-Max2, and to a lesser degree FW-Min2 were identified as the most sensitive parameters with a similar performance to the ETP-based APC resistance assay.

Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk.

Combined oral contraceptives (COCs) induce several changes in the levels of coagulation factors. The levels of procoagulant factors are often increased, while levels of anticoagulant factors are decreased. Fibrinolysis is also affected, even if the effect seems to be more counterbalanced by opposite regulation of profibrinolytic and antifibrinolytic factors. These effects on hemostasis are more pronounced with third- or fourth-generation COC compared with second-generation COC. Venous thromboembolism (VTE) risk increases when multiple risk factors, including genetic and environmental, are present simultaneously. COC use causes changes in coagulation that modify the prothrombotic state induced by preexisting hemostatic alterations in a supra-additive manner. Therefore, testing appears to be of importance not only before implementing COC but also to monitor any potential thrombogenicity induced by COC therapy. Inherited genetic factors, such as factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C or protein S deficiencies, non-O blood group, as well as CYP2C9*2 and the rs4379368 mutations, have all been identified as genetic predictive risk factors of VTE in women. Nevertheless, the screening of these genetic biomarkers is not capable of assessing the phenotypic expression of the risk. This review will focus on the different options for screening the thrombogenic status in this population. Specific attention will be given to the endogenous thrombin potential-based activated protein C resistance, a test aiming at assessing the thrombogenicity induced by hormonal therapies and inherited or acquired thrombophilia.

Assessment of the Dose-Response Relationship between Meal Protein Content and Postprandial Thermogenesis: Effect of Sex and the Oral Contraceptive Pill.

Implementation of efficacious dietary interventions to regulate energy balance requires understanding of the determinants of individual response. To date, information regarding individual variability in response to elevated meal protein content is lacking. This study investigates whether sex and/or oral contraceptive pill (OCP) use play a role in the response to elevated meal protein in 21 healthy young adults (seven men, seven women not taking OCP, and seven women who were OCP users). Participants consumed each of three standardized isocaloric (590 kcal) meals of differing protein content (11, 23, 31% kcal protein). Resting energy expenditure (EE), respiratory quotient (RQ), hunger and satiety were measured at baseline (fasting) and during 180 min postprandial. Whilst significant dose-response increases in EE were observed in men, meal protein-induced EE in women without OCP reached a maximum at <23% protein. Women taking OCP reported lower postprandial fullness than women without OCP, despite similar body size, but also, most notably, no significant difference in EE response between any of the meals. Whilst the mechanisms underpinning this thermogenic inflexibility in response across a wide-range (three-fold) of protein meal content require further investigation, this highlights the need for careful consideration of factors that may influence an individual's metabolic response to dietary interventions aimed at optimising postprandial thermogenesis for body weight regulation.

Determinants of hair cortisol and hair cortisone concentrations in adults.

BACKGROUND: The analysis of hair cortisol concentrations (HairF) is a promising new tool for the assessment of long-term cortisol. With the development of multiple steroid analyses by means of liquid chromatography tandem-mass spectrometry (LC-MS/MS), the analysis of cortisone in hair (HairE) has also been facilitated. However, the influence of various types of determinants on HairF and HairE is still largely unknown. This study systematically assesses the influence of sociodemographic, health, lifestyle, and hair (treatment) characteristics on HairF and HairE. METHOD: Data of 760 psychiatrically healthy participants (71.8% female, mean age 45.89 years) of the Netherlands Study of Depression and Anxiety (NESDA) were used. HairF and HairE were measured in the proximal 3 cm of scalp hair, using LC-MS/MS. FINDINGS: HairF and HairE strongly correlated. In simple linear regressions, HairF and HairE were higher in older age, in presence of diabetes mellitus, and in men compared to women. More frequent washing of the hair was associated with lower HairF and HairE. Darker hair colours were associated with higher HairF and HairE. An effect of season and of use of oral contraceptives was found for HairF. After full mutual adjustment, only age, presence of diabetes mellitus, hair washing frequency, and season remained significant determinants of HairF. INTERPRETATION: This large-scale study shows that HairF and HairE are upregulated in older age and in the presence of diabetes mellitus. This suggests that these levels are important for somatic health and should be taken into account when using hair corticosteroid analysis in future studies.

Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide.

BACKGROUND: The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. STUDY DESIGN: We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose-response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. RESULTS: We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose-response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl estradiol (EE). CONCLUSION: This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition potency and a summary of all preparations currently on the world market, including their regimens and their combinations with EE.

Estradiol valerate/dienogest: a novel oral contraceptive.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of the new oral contraceptive estradiol valerate/dienogest. DATA SOURCES: Searches of PubMed (1966-July 2011) and International Pharmaceutical Abstracts (1970-July 2011) were conducted using the key words estradiol valerate, dienogest, Natazia, and Qlaira. Bibliographies of retrieved articles were reviewed to identify additional references. STUDY SELECTION AND DATA EXTRACTION: All identified studies published in English and involving efficacy and safety of estradiol valerate/dienogest as an oral contraceptive were reviewed. DATA SYNTHESIS: Estradiol valerate/dienogest is a 4-phasic oral contraceptive approved for the prevention of pregnancy. The 4-phasic design allows for acceptable cycle control with this hormonal combination. In efficacy trials of estradiol valerate/dienogest in women aged 18-35 years, the Pearl Index ranged from 0.40 to 1.64, a range comparable to that of other combination oral contraceptives. The safety profile was also similar to that of other oral contraceptives, with headache, metrorrhagia, breast tenderness, nausea or vomiting, acne, and weight gain reported as the most common adverse effects. Menstrual bleeding patterns and cycle control with estradiol valerate/dienogest were comparable to those of a monophasic oral contraceptive containing ethinyl estradiol/levonorgestrel. Estradiol valerate/dienogest differs from other oral contraceptives in that it necessitates more stringent dosing guidelines for maximum contraceptive efficacy. New starts should be on the first day of menses only, and a back-up method of contraception is required for the first 9 days, as compared to 7 days with other oral contraceptives. Back-up contraception is usually required for any pill taken more than 12 hours later than scheduled. CONCLUSIONS: Estradiol valerate/dienogest is an effective oral contraceptive. Because it has more stringent start times and requires a longer duration of backup contraception and stricter adherence, estradiol valerate/dienogest should be reserved for patients who are intolerant of other combination oral contraceptives.

Effect of administration of oral contraceptives on the synthesis and breakdown of myofibrillar proteins in young women.

Oral contraceptive (OC) treatment has an inhibiting effect on protein synthesis in tendon and muscle connective tissue. We aimed to investigate whether OC influence myofibrillar protein turnover in young women. OC-users (24±2 years; Lindynette® n=7, Cilest® n=4) and non-OC-users (controls, 24±4 years n=12) performed one-legged kicking exercise. The next day, the myofibrillar protein fractional synthesis rate (FSR) was measured using stable isotopic tracers ((13)C-proline) while the subjects were fed standardized nutrient drinks. Simultaneously, a marker for myofibrillar protein breakdown, 3-methyl-histidine (3-MH), was measured in the interstitial fluid of the vastus lateralis. Measurements were performed in both legs. In general, myofibrillar protein FSR was lower in OC-users (two-way analysis of variance, P<0.05), although the difference seemed to depend on the OC type. Interstitial 3-MH in the skeletal muscle was not different between groups and did not vary by OC type. Exercise did not change myofibrillar protein FSR or 3-MH concentrations. Serum androstenedione and bioavailability of testosterone were lower in OC-users. In conclusion, the results indicate that the use of OC has an inhibiting effect on myofibrillar protein synthesis and the magnitude of the effect may depend on the type of OC. In contrast, there was no effect of OC on myofibrillar protein breakdown in the fed state.

Further assessment of 17alpha-ethinyl estradiol as an inhibitor of different human cytochrome P450 forms in vitro.

17alpha-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC(50) (concentration of inhibitor required to decrease activity by 50%) values were obtained with recombinant CYP1A1 (rCYP1A1) [IC(50(total)) = IC(50(free)) = 2.7 microM] and CYP2C19 activity in human liver microsomes (HLM) [IC(50(total)) = 4.4 microM; IC(50(free)) = 2.8 microM]. For rCYP1A1, formal inhibition studies revealed that EE was a competitive inhibitor [K(i(free)) = 1.4 microM]. All the other IC(50) values were greater than 8.0 microM, and the weakest inhibition was observed with CYP1A2 activity in HLM (IC(50(free)) > 39 microM). In agreement, the IC(50) characterizing the inhibition of melatonin (MEL) 6-hydroxylation in human intestine microsomes (CYP1A1-catalyzed) was lower than that of HLM (0.91 versus >40 microM). Because EE is known to affect the pharmacokinetics of CYP2C19 probe drugs, this result raises the possibility that the concentration of EE during first pass may exceed 1000 nM, sufficient to affect CYP1A1 and CYP2C19, with less impact on CYP3A4 and other P450s. The results implicate intestinal CYP1A1, and possibly CYP2C19, as the loci of EE drug interactions with highly extracted drugs like MEL. Overall, it is very difficult to rationalize drug interactions involving EE based on direct inhibition of CYP2B6 (e.g., selegiline) and hepatic CYP1A2 (e.g., MEL, tizanidine, caffeine, and theophylline).

Factors that influence the rate of epithelial maturation in the cervix in healthy young women.

PURPOSE: To examine the longitudinal changes in the epithelial topography of the cervix in healthy young women; and to determine the sociodemographic, behavioral, and biological factors associated with the rate of cervical epithelial maturation. METHODS: Healthy young women were enrolled from October 2000 to September 2002 as part of a larger study of human papillomavirus (HPV). At interval visits, interviews, infection testing, and colpophotography (3% acetic acid; 10x, 16x magnifications) were performed. Areas of total cervical face and cervical immaturity, defined as columnar and early squamous metaplasia, were quantitatively measured using computerized planimetry. Cervical immaturity was expressed as percentage of total cervical face. This analysis includes the first consecutive 145 women with greater than 10% immaturity at baseline. The rate of cervical maturation was defined as change in percent-immaturity. Predictors included sociodemographics, sexual behaviors, and infections. Data analyses included multivariate generalized linear models with repeated measures. RESULTS: The baseline mean age was 17.8 years. Colpophotographs were available from 815 total visits, representing 2.7 years mean follow-up per woman and 5.9-month mean intervals. Women began the study with a median of 39% immaturity and ended with 8% immaturity. After adjusting for time and baseline percent-immaturity, an increased rate of cervical maturation was associated with oral contraceptive pill use (parameter estimate -.023, p =.04) and smoking (-.039, p =.01). CONCLUSIONS: Cervical maturation was documented during relatively short time periods for the vast majority of these women. Oral contraceptive pills and smoking may accelerate the maturational process, representing increased cell proliferation and thus a possible greater vulnerability to HPV.

Changes in blood pressure, BMI and ECG Patterns in women using low-dose contraceptives.

OBJECTIVE: To determine the cardiovascular risk factors in users of second generation contraceptives by recording changes in body mass index, blood pressure and electrocardiogram. DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: The National Institute of Fertility Research Centers at Jinnah Postgraduate Medical Center and PIB Maternity Home Karachi, from July 1997 to 1999. MATERIALS AND METHODS: Sixty four women volunteered for this study (age range 20-35 years), belonging to low-income group with similar socio-cultural background. The Body Mass Index (BMI) was calculated by measuring height and weight of the subjects; systolic and diastolic blood pressure and ECG recording by standard method. The group means, standard deviations and coefficient correlation for interrelationship among variables in respective groups of subjects were calculated using relevant statistical method and software program. RESULTS: There was no significant difference between BMI of two types of contraceptive users as compared to non users; but BMI was significantly correlated with both systolic and diastolic blood pressures in injectable users as compared to controls. ECG alterations frequently observed in contraceptive users (40%) as compared to controls were normal findings. CONCLUSION: It was observed that women aged < 30 years and using contraceptives for more than three years had a tendency to gain weight and developed a mild increase in systolic and diastolic blood pressures.

Aerodynamic assessment of young women's voices as a function of oral contraceptive use.

OBJECTIVE: To examine possible differences in glottal airflow parameters according to oral contraceptive (OC) use. SUBJECTS AND METHODS: The participants included 16 women, 20-24 years of age. Eight women were taking a triphasic OC; the remaining 8 women were not taking any form of oral contraception (NOC). All participants were recorded on days 7 and 14 of their menstrual cycle. Three repetitions of the sustained vowel /a/ were obtained using a circumferentially vented respiratory face mask connected to a wide-band pressure transducer. Measures of peak flow, minimum flow, alternating flow, fundamental frequency (F(0)) and relative sound pressure level were obtained. RESULTS: A multivariate analysis of variance with sound pressure level as a covariate revealed no significant effect of day of recording upon the dependent measures. As a group, the OC women exhibited significantly higher F(0), peak and alternating flow rates compared to the NOC women. Removal of data outliers from the OC women resulted in similar airflow rates for both groups. CONCLUSION: The findings from this preliminary study did not support the use of glottal airflow measures to distinguish OC women from NOC women. Differences in F(0) findings may reflect hormonally mediated changes in laryngeal tissue and warrant further investigation.

Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study.

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

Ruling out deep venous thrombosis in primary care. A simple diagnostic algorithm including D-dimer testing.

In primary care, the physician has to decide which patients have to be referred for further diagnostic work-up. At present, only in 20% to 30% of the referred patients the diagnosis DVT is confirmed. This puts a burden on both patients and health care budgets. The question arises whether the diagnostic work-up and referral of patients suspected of DVT in primary care could be more efficient. A simple diagnostic decision rule developed in primary care is required to safely exclude the presence of DVT in patients suspected of DVT, without the need for referral. In a cross-sectional study, we investigated the data of 1295 consecutive patients consulting their primary care physician with symptoms suggestive of DVT, to develop and validate a simple diagnostic decision rule to safely exclude the presence of DVT. Independent diagnostic indicators of the presence of DVT were male gender, oral contraceptive use, presence of malignancy, recent surgery, absence of leg trauma, vein distension, calf difference and D-dimer test result. Application of this rule could reduce the number of referrals by at least 23% while only 0.7% of the patients with a DVT would not be referred. We conclude that by using eight simple diagnostic indicators from patient history, physical examination and the result of D-dimer testing, it is possible to safely rule out DVT in a large number of patients in primary care, reducing unnecessary patient burden and health care costs.

Potential bias due to excluding oral contraceptive users when estimating menstrual cycle characteristics.

Women take oral contraceptives for contraception but also for menstrual dysfunction treatment. This raises the question of whether or not women with menstrual dysfunction are underrepresented in analyses of menstrual function because oral contraceptive users are excluded. To explore this, the authors examined the history of oral contraceptive use among 1322 Black women and White women, aged 35-49 years, who had been randomly selected from a large health plan's membership in Washington, DC, between 1996 and 1999. The women reported whether they took oral contraceptives during their teens, twenties, and thirties, and if so, the reason they took them (prevent pregnancy, medical problem, or both). They also reported their usual menstrual cycle length when not using oral contraceptives during these decades. The prevalence of oral contraceptive use strictly for medical problems was low for both Black women and White women (4-9% of women), and the distributions of usual cycle length were similar for women who did and did not take oral contraceptives. Thus, there was little evidence of substantial bias of estimates of cycle characteristics caused by excluding oral contraceptive users from analyses of menstrual function. However, our data indicate that, with only a few additional questions, information on usual menstrual cycle characteristics can be collected and used to evaluate bias in any given study.

Effects of oral contraceptive use on body mass index and blood pressure among female villagers in north-east Thailand.

The use of contraceptives has become prevalent among females in Thailand in the past 20 years, and oral contraceptive use has been suggested to trigger changes in fat intake, energy expenditure, fat metabolism and blood pressure. Based on field investigations of 391 married women aged 20 years or over in Yasothon Province, North-east Thailand, this study aims to elucidate the effects of oral contraceptive use on body mass index (BMI: kg/m2) and blood pressure, taking into account reproductive histories and socioeconomic conditions. The proportion of obese (BMI > or = 25) subjects was high in the age groups 30-39, 40-49 and 50-59, accounting for, respectively, 39.4%, 51.1% and 48.5% of these populations. The proportion of women with hypertension (90/140 mmHg) was 23.7%, 18.5% and 26.2% in the 40-49, 50-59 and 60-69 age groups. Current contraceptive practices in the studied population included sterilization by operation, oral contraception and injection. These methods accounted for 43.0%, 12.8% and 8.2% of the population, respectively. Sociodemographic factors such as reproductive history, years of education and household income were not significantly related to BMI or to blood pressure (ANOVA with age adjustment). In contrast, oral contraceptive users had significantly higher BMIs and diastolic blood pressures (p<0.01, ANOVA with age adjustment). Multiple regression analysis also revealed that oral contraceptive use was a weak but significant contributing factor to both high BMI and blood pressure when sociodemographic factors were taken into account and controlled for statistically. It can thus be concluded that the use of contraceptive pills, which contain oestrogen and progestin and are provided free of charge to Thai women, tend to increase BMI and to elevate blood pressure.

Bleeding patterns after immediate vs. conventional oral contraceptive initiation: a randomized, controlled trial.

OBJECTIVE: To compare bleeding patterns after immediate vs. conventional oral contraceptive (OC) initiation. DESIGN: Randomized controlled trial. SETTING: University-based clinic. PATIENT(S): One hundred thirteen women initiating combination OCs. INTERVENTION(S): Participants received a 4-month supply of a monophasic 35-microg ethinyl E(2) (EE) OC and a bleeding diary, were randomized to immediate or conventional OC start, underwent monthly telephone follow-up, and after 90 days returned the diary and completed an exit interview. MAIN OUTCOME MEASURE(S): Total number of bleeding-spotting days, using the World Health Organization 90-day reference period method. Comparisons were made by trial assignment (immediate vs. conventional) and cycle day of OC initiation (day 8+ vs. days 1-7). RESULT(S): There was no significant difference in the number of bleeding-spotting days (mean difference: -0.5 days; 95% CI: -3.4 to 2.3) or any other bleeding parameter between the immediate and conventional starters, or days 1-7 and day 8+ starters. CONCLUSION(S): Immediate start of OCs does not induce bleeding patterns different from conventional starting regimens. Concern about adverse bleeding patterns should not be considered a justification for instructing women to wait until menses before starting OCs.

Effects of race, cigarette smoking, and use of contraceptive medications on resting energy expenditure in young women.

The prevalence of obesity is higher in Black women than in White women (JAMA 1994;272:205-11; Arch Pediatr Adolesc Med 1995;149:1085-91). Although it has been shown that Black women have a lower resting energy expenditure (REE), factors affecting REE remain unclear. This 1996-1997 study in Cincinnati, Ohio, assessed racial differences in REE and their determinants in a biracial cohort of 152 healthy young women aged 18-21 years. Two indirect calorimetric measurements were obtained during two overnight hospital admissions 10-14 days apart. Body composition was measured by using dual-energy x-ray absorptiometry. Mean REE (adjusted for body composition, smoking, and contraceptive medication use) was significantly (p = 0.04) lower by 71 kcal/day in Black women (1,453 (standard error, 21) kcal/day) than in White women (1,524 (standard error, 19) kcal/day). Smoking was associated with a REE that was 68 kcal/day higher for both groups (p = 0.03). A trend (p = 0.07) toward increased REE (by 46 kcal/day) was found with contraceptive medication use. In conclusion, young Black women had a significantly lower REE than did White women. Cigarette smoking significantly increased REE. The apparent presence of a more parsimonious energy metabolism in Black women suggests that maintenance of energy homeostasis requires particular vigilance in this high-risk population.

The induction of amenorrhoea.

A survey has shown that many women favour eliminating menstruation and it has been suggested that therapeutic induction of amenorrhoea might be an advantage in female personnel mobilised for war. The traditional method has been to take the oral contraceptive pill continuously. This produces weight gain and other side-effects; spotting and breakthrough bleeding can be a problem initially. The method is however cheap. The Gonadotrophin Releasing Hormone (GnRH) analogue, goserelin, is extremely effective, produces less side-effects, but it is very expensive. Two synthetic steroids, danazol and gestrinone, are moderately effective, have a variety of prominent side-effects and are also quite expensive. With all these drugs normal menstruation resumes in the cycle after they are discontinued. Although goserelin has many advantages over the continuously taken contraceptive pill, its cost precludes it from consideration as a means of eliminating menstruation.

PIP: The Royal Army Medical Corps (RAMC) of the UK is considering offering women in the Army the option of inducing amenorrhea especially those in war. Logistics problems of supplying sufficient sanitary protection makes inducing amenorrhea in these women an advantage. It is important that the Royal Army not force servicewomen ready for war to agree to chemical induction of amenorrhea, however. A survey of civilian women shows that 80% liked the notion of eliminating menstruation. continuous combined oral contraceptive (COC) therapy induces amenorrhea, but it poses some side effects including bleeding and spotting, 2 kg weight gain, breast tenderness, depression, and headaches. 12 weeks of COC therapy costs range form 2 to 6 pounds. The synthetic androgen used to treat endometriosis, danazol, may also induce amenorrhea at daily doses of 800 mg. It causes various side effects including reduced breast size, flushing, sweating, loss of libido, acne, weight gain, edema, hirsutism, and voice change. 12-week danazol therapy costs about 200 pounds. Another drug with androgenic, antigonadotrophic, antiestrogenic, and antiprogestogenic properties which is also used to treat endometriosis, gestrinone, in another possible amenorrhea inducer at 2 doses of 2.5-5 mg/week. Side effects are similar to those of danazol. In 1 study, all 20 patients developed acne and seborrhea. Its 12 week costs are considerably more than danazol and COC therapy (450 pounds). Intermittent administration of 2 gonadotropin releasing hormone (GnRH) analogues, buserelin and goserelin, suppresses production of gonadotropins. Health workers need to inject 3.6 mg goserelin every 28 days while they administer buserelin subcutaneously or intranasally. the leading side effect on both GnRH analogues is not flushes. 12-week therapy is about 375 pounds. Fertility is restored after discontinuation of all the aforementioned therapies. The GnRH analogue goserelin is the most effective therapy, but the cost factor causes the Royal Army to favor COCs.

Desogestrel and gestodene in oral contraceptives: 12 months' assessment of carbohydrate and lipoprotein metabolism.

We examined the influence on carbohydrate and lipoprotein metabolism of oral contraceptives (OCs) containing two new third-generation progestogens, desogestrel and gestodene. This was a prospective randomized study in which monophasic combinations of 20 micrograms ethinyl estradiol (E2) and 150 micrograms desogestrel or 30 micrograms ethinyl E2 plus 75 micrograms gestodene were administered to 15 and 19 healthy women, respectively. An oral glucose tolerance test including measurement of insulin response was performed before treatment and after 3, 6, and 12 months of treatment. We also determined fasting plasma concentrations of total cholesterol; high-density lipoprotein cholesterol, including the subfractions high-density lipoprotein2 cholesterol and high-density lipoprotein3 cholesterol; low-density lipoprotein cholesterol; very low-density lipoprotein cholesterol; and triglycerides. A transient deterioration of glucose tolerance was observed despite unchanged levels of insulin after treatment with both compounds for 3 months. In both groups plasma levels of triglycerides, very low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol increased significantly after 3 months. After 12 months, a significant increase in the high-density lipoprotein cholesterol/total cholesterol ratio was observed in the ethinyl E2-desogestrel group, and no persistent changes in low-density lipoprotein cholesterol could be demonstrated in any of the groups. Our results indicate that treatment with either compound for 12 months has no effect on carbohydrate or lipoprotein metabolism known to increase the risk of cardiovascular disease.