The drospirenone (DRSP)-only pill: clinical implications in the daily use.

OBJECTIVES: Progestins used in contraception are either components of combined hormonal contraceptives or are used as a single active ingredient. Progestins are highly effective in long-term contraception and have a very good safety profile with very few contraindications. METHODS: An oestrogen-free ovulation inhibitor POP has been authorised in the USA and the EU. It contains 4 mg of drospirenone (DRSP). The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular- phase levels, preventing oestrogen deficiency. RESULTS: Clinical trials have demonstrated high contraceptive effectiveness, a very low risk of cardiovascular risk events and a favourable bleeding pattern. Due to the long half-life of DRSP (30-34 h), the effectiveness is maintained even in case of a forgotten pill on a single occasion. Studies involving deliberate 4 days in one cycle 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. CONCLUSIONS: This review article will describe the clinical impact in the daily use of the 4 mg DRSP only pill and the resulting data on the effectiveness and safety of this hormonal contraceptive.

The 4 mg drospirenone-only pill improves the bleeding profile in comparison to 0.075 mg desogestrel and achieves high contraceptive efficacy even with a 24 h missed pill window.

[MHT: How and how long in healthy women above 65?] / Menopausale Hormontherapie: Wie und wie lange für gesunde Frauen über 65?

MHT: How and how long in healthy women above 65? Abstract. In Europe, women spend more than one third of their lifetime in the postmenopause which is characterized by chronic estrogen deficiency. About 80 % of them suffer from vasomotor symptoms which can last for up to twelve years or more. Menopausal hormone therapy (MHT) with sexual steroids is the most effective treatment resulting in a reduction of hot flushes and an improvement of quality of life. Today, a large proportion of women is not treated adequately as demonstrated by a marked decline of MHT-prescriptions. The postmenopause is not only associated with climacteric symptoms, but also with long-term risks, such as cardiovascular events, osteoporosis, cognitive dysfunction or diabetes mellitus. Numerous studies have shown beneficial effects of MHT on many of these diseases and on mortality, provided that treatment has been initiated close to the onset of menopause. Accordingly, some investigators have postulated a possible role of MHT in primary prevention. However, concerning long-term beneficial effects of MHT in women beyond the age of 65 years, the optimal duration of MHT is still unknown. Consequently, the duration of MHT should always be planned individually after thorough consideration of potential benefits and risks in agreement with the patient. Especially with advancing age transdermal application of estrogens seems to be the best option because of less vascular risks. There is no apodictic limitation of maximal duration of MHT.

Effectiveness and safety of follitropin alfa (Ovaleap®) for ovarian stimulation using a GnRH antagonist protocol in real-world clinical practice: a multicenter, prospective, open, non-interventional assisted reproductive technology study.

BACKGROUND: The use of recombinant human follicle-stimulating hormone (r-hFSH) in ovarian stimulation protocols for infertility treatment in assisted reproductive technology (ART) clinical practice is well established. More recent advancements include the availability of biosimilar r-hFSH products, which expand the choices available to healthcare practitioners and patients. Better understanding of how such a product contributes to routine clinical practice is valuable to help prescribers make informed treatment choices. The objective of this study was to examine the effectiveness and safety of ovarian stimulation (OS) with follitropin alfa (Ovaleap®) for routine IVF or intracytoplasmic sperm injection treatment in gonadotropin-releasing hormone (GnRH) antagonist cycles in real-world ART clinical practice. METHODS: This non-interventional, multicenter, prospective study was initiated in 34 specialized reproductive medicine centers in Germany. Eligible women were 18-40 years old with a body mass index < 30 kg/m2, menstrual cycle 24-35 days and anti-Müllerian hormone ≥1 ng/mL, who were undergoing a first OS cycle exclusively with Ovaleap® during routine ART using a GnRH antagonist protocol. Primary effectiveness outcomes were number of retrieved oocytes after OS and clinical pregnancy rate (CPR). Secondary outcomes included fertilization rate, number of transferred embryos, live birth delivery rate, safety, and user satisfaction with the Ovaleap® pen. RESULT(S): Of 507 women screened, 463 received at least 1 dose of Ovaleap® and 439 had Visit 2 data (per protocol population; PPP). The mean(±SD) number of retrieved oocytes was 11.8 ± 7.2 (PPP). The CPR among women with documented embryo transfer was 41.3% (158/383), resulting in a live birth delivery rate of 31.6% (138/437) among PPP patients with available follow-up information. Overall, 8.6% (40/463) of women reported ≥1 adverse drug reaction. Ovarian hyperstimulation syndrome occurred in 23 (5.0%) patients, rated mild in 14 (3.0%), moderate in 8 (1.7%), and severe in 1 (0.2%). Patients reported high user satisfaction and high convenience with use of the Ovaleap® pen. CONCLUSION: The effectiveness and safety of OS with Ovaleap® in a GnRH antagonist protocol were extended to real-world ART clinical practice for the first time. TRIAL REGISTRATION: Registered on 22 June 2016 (retrospectively registered) at ClinicalTrials.gov (NCT02809989).

Extended-cycle versus conventional treatment with a combined oral contraceptive containing ethinylestradiol (30 µg) and levonorgestrel (150 µg) in a randomized controlled trial.

The objective was to assess efficacy and safety of a combined oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in an extended-cycle vs. a conventional-cycle regimen. This first European randomized, active controlled, open, prospective, parallel-group trial was conducted in 48 German gynecological centers. 1,314 healthy, sexually active women aged 18-35 years were randomized. With an unadjusted PI of 0.483 (upper 95% CI: 1.237), the extended-cycle regimen fulfilled the contraceptive efficacy of EE/LNG, the requirements of the European Medicines Agency. The mean total number of bleeding days per year was significantly lower in the extended-cycle vs. the conventional-cycle regimen. Analyses of bleeding patterns showed a reduced total number of bleeding/spotting days per year in the extended-cycle vs. the conventional-cycle regimen. Cycle-associated complaints and AE were comparable in both groups. Both regimens were very well accepted. The extended-cycle regimen of EE/LNG was effective and well tolerated resulting in a lower number of bleeding days and a favorable bleeding pattern compared to the conventional-cycle regimen.

Estradiol regulates human QT-interval: acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking.

BACKGROUND: Modulation of cardiac repolarization by sexual hormones is controversial and hormonal effects on ion channels remain largely unknown. In the present translational study, we therefore assessed the relationship between QTc duration and gonadal hormones and studied underlying mechanisms. METHODS AND RESULTS: We measured hormone levels and QTc intervals in women during clomiphene stimulation for infertility and women before, during, and after pregnancy. Three heterozygous LQT-2 patients (KCNH2-p.Arg752Pro missense mutation) and two unaffected family members additionally were studied during their menstrual cycles. A comprehensive cellular and molecular analysis was done to identify the mechanisms of hormonal QT-interval regulation. High estradiol levels, but neither progesterone nor estradiol/progesterone ratio, inversely correlated with QTc. Consistent with clinical data, in vitro estradiol stimulation (60 pmol/L, 48 h) enhanced IKCNH2. This increase was mediated by estradiol receptor-α-dependent promotion of KCNH2-channel trafficking to the cell membrane. To study the underlying mechanism, we focused on heat-shock proteins. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished estradiol-induced increase in IKCNH2. Geldanamycin had no effect on KCNH2 transcription or translation; nor did it affect expression of estradiol receptors and chaperones. Estradiol enhanced the physical interaction of KCNH2-channel subunits with heat-shock proteins and augmented ion-channel trafficking to the membrane. CONCLUSION: Elevated estradiol levels were associated with shorter QTc intervals in healthy women and female LQT-2 patients. Estradiol acts on KCNH2 channels via enhanced estradiol-receptor-α-mediated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of human ventricular repolarization and open novel therapeutic avenues.

Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ.

Detection of disseminated tumor cells (DTCs) in bone marrow is an independent prognostic factor in primary breast cancer. Here, we conducted a proof-of-principle study to evaluate whether this tumor cell spread occurs already in patients with ductal carcinoma in situ (DCIS). After preoperative screening by stereotactic core biopsy, 30 consecutive women with DCIS were included. Bone marrow aspirates, taken at the time of primary surgery, were subjected to DTC detection by a standardized immunoassay using the established monoclonal anti-cytokeratin antibodies A45-B/B3 and AE1/AE3. DTCs were detected in 4 of 19 cases of pure DCIS (21.1%) and in four of seven cases of DCIS with microinvasion (57.1%). After a median follow-up time of 22 months, two initially DTC-positive patients suffered from contralateral carcinoma and contralateral DCIS at months 12 and 30, respectively, whereas the remaining patients were relapse free. Thus, hematogenous tumor cell dissemination into bone marrow is an early event in breast cancer development.

Correction: Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone.

[This corrects the article DOI: 10.1055/a-1471-4408.][This corrects the article DOI: 10.1055/a-1471-4408.].

Oral Progestins in Hormonal Contraception: Importance and Future Perspectives of a New Progestin Only-Pill Containing 4 mg Drospirenone.

Hormonal contraceptives are an effective and safe method for preventing pregnancy. Progestins used in contraception are either components of combined hormonal contraceptives (tablets, patches or vaginal rings) or are used as a single active ingredient in progestin mono-preparations (the progestin-only pill (POP), implants, intrauterine systems or depot preparations). Progestins are highly effective in long-term contraception when used properly, and have a very good safety profile with very few contraindications. A new oestrogen-free ovulation inhibitor (POP) has recently been authorised in the USA and the EU. This progestin mono-preparation contains 4 mg of drospirenone (DRSP), which has anti-gonadotropic, anti-mineralocorticoidic and anti-androgenic properties. The hormone administration regimen of 24 days followed by a 4-day hormone-free period was chosen to improve bleeding control and to maintain oestradiol concentrations at early follicular-phase levels, preventing oestrogen deficiency. Clinical trials have demonstrated a high contraceptive effectiveness, a very low risk of cardiovascular side effects and a favourable menstrual bleeding pattern. Due to the long half-life of DRSP (30 - 34 hours), the effectiveness of the preparation is maintained even if a woman forgets to take a pill on a single occasion. Studies involving deliberate 24-hour delays in taking a pill have demonstrated that ovulation inhibition is maintained if a single pill is missed. Following a summary of the current status of oestrogen-free contraception, this review article will describe the clinical development programme of the 4 mg DRSP mono-preparation and the resulting data on the effectiveness and safety of this new oestrogen-free oral hormonal contraceptive.

Prescribing preferences and personal experience of female gynaecologists in Germany and Austria regarding use of extended-cycle oral contraceptives.

OBJECTIVES: To investigate prescribing preferences and personal experience of female gynaecologists with extended-cycle use of combined oral contraceptives (COCs) in Germany and Austria. METHODS: A questionnaire on prescribing patterns and personal experience with extended COC regimens was delivered to female gynaecologists practising in Germany and Austria. RESULTS: Of 2,500 delivered questionnaires, 1,113 were returned. After exclusion of 22 invalid questionnaires, the remaining 1,091 (43.6% of delivered questionnaires) remained eligible for analysis and were considered as the full analysis set (100%). Nearly all gynaecologists (97%) reported prescription of extended-cycle regimens to their patients, independent of their personal experience as users. The main medical reasons for prescription were cycle-related headache (93.8%), dysmenorrhoea (88.2%), cycle-related complaints (74.5%), and hypermenorrhoea (70.9%). In total, 863 gynaecologists had personally used COCs, 321 (37.2%) in extended-cycle regimen. The most commonly employed combinations were 30 µg ethinylestradiol (EE) + 2 mg dienogest (n = 114; 37.5%) and 30 µg EE + 3 mg drospirenone (n = 69; 22.7%). CONCLUSIONS: Although considered off-label use, extended-cycle use of COCs is widely prescribed and personally used by German and Austrian female gynaecologists. The lack of personal experience with extended-cycle use does not impair the prescribing habit of gynaecologists with regard to extended-cycle regimens.

Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters: conventional vs. extended-cycle use.

BACKGROUND: This study was conducted to investigate the effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters. STUDY DESIGN: Thyroid and androgen parameters were measured in 59 women treated with a monophasic combined oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or according to an extended-cycle regimen (four extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle, or on Days 82-84 of the first and fourth extended cycle. RESULTS: At both time points, the serum concentrations of thyroxine-binding globulin were elevated by about 65% in both treatment regimens. Likewise, both groups showed an increase in total triiodothyronine (T3) and total thyroxine (T4) by 30-40%, and no change in free T4. Until the 12th month of conventional treatment, the level of free T3 remained unchanged but decreased slightly during the extended-cycle regimen. In both groups there was a rise of sex hormone-binding globulin by 210-230% after 3 months and by 220-250% after 12 months. The levels of total testosterone were reduced by about 40% and those of free testosterone by 55-65% after 3 and 12 months. CONCLUSION: The results suggest that, during conventional and extended-cycle treatment with EE/DNG, a steady state in the effects on thyroid hormones and androgen parameters was reached within 3 months and that the changes in the various hormonal parameters did not substantially differ between conventional and extended-cycle regimen.

Effects of conventional or extended-cycle regimen of an oral contraceptive containing 30 mcg ethinylestradiol and 2 mg dienogest on various hemostasis parameters.

BACKGROUND: The study was conducted to investigate the effect of a combined oral contraceptive (COC) containing 30 mcg ethinylestradiol and 2 mg dienogest with two different regimens on various hemostasis variables. STUDY DESIGN: Hemostatic parameters were measured in 59 women treated with a monophasic COC containing 30 mcg ethinylestradiol and 2 mg dienogest (EE/DNG) either conventionally (13 cycles with 21 days of treatment+7 days without hormones) or with an extended-cycle regimen (4 extended cycles with 84 days of continuous administration of EE/DNG, followed by a hormone-free interval of 7 days). Blood samples were taken on Days 21-26 of the preceding control cycle and on Days 19-21 of the 3rd and 13th conventional cycle or on Days 82-84 of the first and fourth extended cycle. RESULTS: After 3 and 12 months, significant increases in fibrinogen (20%), factor VII antigen (50-60%), factor VII activity (45%), activated factor VII (30-45%) and factor VIII activity (10-20%) occurred in both treatment regimens. In both groups, there was a small but significant decrease in the level and activity of antithrombin, a 20-25% decrease in total and free protein S and a 15-20% rise in the level and activity of protein C, but no significant change of the thrombin-antithrombin complex. A significant over-time rise by about 25% of prothrombin fragment 1+2 occurred only in the extended-cycle group, but this effect did not differ significantly from that observed during conventional treatment. Plasminogen was elevated by 50% in both groups, while tissue-plasminogen activator (t-PA) activity rose by 15% in the conventional group and by 25-30% in the extended-cycle group. In both groups, t-PA antigen was reduced by about 30% and plasminogen activator inhibitor-1 by 40-60%. The levels of the plasmin-antiplasmin complex rose by 30-40% and those of D-dimers by 20-55%. The prothrombin time was slightly increased and the activated partial thromboplastin time was slightly decreased. CONCLUSION: In general, these results were in agreement with those observed during treatment with other COCs. The study demonstrated that during conventional and extended-cycle treatment with EE/DNG, a steady-state in the effects on hemostasis variables was reached within 3 months, and that the effects observed after 3 and 12 months of treatment did not substantially differ between conventional and extended-cycle regimen.

Utero-tubal sperm transport and its impairment in endometriosis and adenomyosis.

The uterus is composed of different smooth muscle layers that serve various functions. First, menstrual debris is expulsed at the time of the menses. Second, sperm is transported in the preovulatory phase to maximize fertility, and third, the human embryo is placed in an adequate setting during implantation. Endometriosis is a gynecologic disorder leading to severe pain symptoms such as severe pain during menstruation (dysmenorrhea), chronic pelvic pain, pain during sexual intercourse (dyspareunia), and abnormal uterine bleeding. Besides, endometriosis is often associated with female infertility and exhibits a massive impairment in the physiology of uterine contractility that can be documented by the in vivo examination method of hysterosalpingoscintigraphy (HSSG). In addition, endometriosis is associated in 80-90% of subjects with adenomyosis and our data clearly indicate that sperm transport is disturbed by hyperperistalsis when at least one focus of adenomyosis can be detected via magnetic resonance imaging (MRI) and turns into dysperistalsis (a complete failure in sperm transport capacity) when diffuse adenomyosis affecting all myometrial uterine muscle layers is detected. Hence, dysperistalsis is significantly associated with reduced spontaneous pregnancy rates. We therefore recommend MRI and HSSG in every sterility workup.

Progestogen therapies: differences in clinical effects?

A large number of estrogen/progestogen preparations are available for the treatment of estrogen-deficiency symptoms. These preparations differ in the route of administration, the type and dose of both the estrogen and progestogen. The only indication for the addition of a progestogen is endometrial protection, but, depending on its chemical structure, a progestogen can either enhance (e.g. hot flushes, gonadotropin release, breast-epithelial proliferation and bone mineral density) or antagonize (e.g. endometrium, arterial wall, lipid metabolism, hepatic protein synthesis and mood) the effects of the estrogen component. Available progestogens differ largely in their hormonal pattern and, in addition to their progestogenic and antiestrogenic action on the endometrium, they can exert androgenic, antiandrogenic, glucocorticoid and/or antimineralocorticoid effects. There are no comprehensive trials comparing directly the modulating effects of the various progestogens, and clinical and epidemiological data do not allow a definite conclusion on the clinical relevance of differences between progestogens.

Adherence with ethinylestradiol 20 µg/drospirenone 3 mg in a flexible extended regimen supported by the use of a digital tablet dispenser with or without acoustic alarm: an open-label, randomized, multicenter study.

OBJECTIVE: To evaluate the effect of a digital dispenser's acoustic alarm function on adherence to ethinylestradiol (EE) 20 µg/drospirenone 3 mg in a flexible extended regimen (EE/drospirenoneFlex) among women in five European countries (France, Germany, Italy, Spain, UK) seeking oral contraception. STUDY DESIGN: Randomized, parallel-group open-label study. METHODS: Women aged 18-35 years received EE/drospirenoneFlex administered in a regimen with cycle lengths of their choice with the aid of a digital pill dispenser over 1 year. In group A (N=250), the dispenser's acoustic alarm was activated (ie, acoustic alarm + visual reminder). In group B (N=249), the acoustic alarm was deactivated (ie, visual reminder only). In addition, the women recorded pill intake daily in diary cards. The primary efficacy variable was the mean delay of daily pill release after the dispenser reminded the woman to take a pill (reference time). Secondary efficacy variables included number of missed pills, contraceptive efficacy, bleeding pattern, tolerability, and user satisfaction. RESULTS: Dispenser data showed a mean (standard deviation [SD]) daily delay in pill release of 88 (126) minutes in group A vs 178 (140) minutes in group B (P<0.0001). Median (lower quartile, Q1; upper quartile, Q3) number of missed pills was 0 (0; 1) in group A vs 4 (1; 9) in group B (P<0.0001). Diary card results revealed similar trends; however, underreporting of missed pills was evident in both groups. No pregnancies were reported during 424 women-years of exposure. Across the two groups, the mean (SD) EE/drospirenoneFlex cycle length was 51.0 (31.8) days with strong regional differences, and the mean (SD) number of bleeding/spotting days was 50.4 (33.0) days. EE/drospirenoneFlex was well tolerated, and 80% of women were satisfied with treatment. CONCLUSION: The dispenser's activated acoustic alarm improved adherence with daily tablet intake of EE/drospirenoneFlex, reducing missed pills. EE/drospirenoneFlex provided effective contraception and a good tolerability profile.

Long-cycle treatment with oral contraceptives.

The conventional regimen of oral contraceptive (OC) use mimics the natural cycles by causing regular withdrawal bleeding, which can be avoided by omission of the hormone-free interval of 7 days. Consequently, long-cycle regimens with continuous administration of OCs for 3 or 6 months followed by a hormone-free interval of 7 days may reduce the frequency of menstruations and cycle-dependent complaints. Surveys have revealed that, despite a higher rate of irregular bleeding, the majority of women prefer the long-cycle regimen to the conventional OC regimen with regular bleeds every 4 weeks because it may improve quality of life. As this regimen increases the contraceptive efficacy to a large degree, continuous treatment with OCs may prevent unintended pregnancies in women who miss a pill or are concomitantly treated with drugs that are able to impair the efficacy of OCs. Postponement of withdrawal bleeding may also reduce or prevent menses-associated disorders such as hypermenorrhoea and dysmenorrhoea, and have beneficial effects in patients with haemorrhagic diathesis, endometriosis, uterine leiomyoma and polycystic ovary syndrome. Continuous use of OCs prevents the cyclic fluctuations of serum levels of ethinylestradiol and progestogen and, hence, the cyclic variations of metabolic serum parameters. Although the long-cycle regimen is initially associated with an elevated rate of irregular bleeding, the total number of bleeding days that require sanitary product protection is lower than during conventional OC treatment. Many physicians tend to prescribe extended OC cycles for postponement of menstruation or reduction of frequency of regular bleeding. This review summarises and examines the available data on OC long-cycle regimens. The data suggest that the rate of treatment-related side effects with OCs according to the long-cycle regimen is similar to that of conventional OC regimens. However, clinical trials are necessary to assess the impact of long-term OC long cycles on safety, particularly the risk of cancer and cardiovascular disease, and fertility after discontinuation of treatment.

Formation of 7 alpha-methyl-ethinyl estradiol during treatment with tibolone.

OBJECTIVE: To investigate whether tibolone, which is orally used for hormone replacement therapy, is transformed to a derivative of ethinyl estradiol (EE). DESIGN: In 10 young women who received 2.5 mg orally administered tibolone daily between cycle day 19 and 25, blood was obtained before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h after the last tablet intake. The concentration of 7 alpha-methyl-EE was determined by the gas chromatography with mass spectrometry method. RESULTS: The results demonstrate that, during daily treatment of women with 2.5 mg tibolone, a small proportion of tibolone is transformed to 7 alpha-methyl-EE. The maximal serum concentrations of 125 +/- 40 pg/mL were in the range of the levels of EE observed during treatment with oral contraceptives containing 30 microg EE. CONCLUSIONS: Caution is advisable when considering treatment with tibolone of postmenopausal women with contraindications for estrogens.

Managing cutaneous manifestations of hyperandrogenic disorders: the role of oral contraceptives.

Cutaneous manifestations of hyperandrogenic disorders (acne, seborrhea, hirsutism and androgenetic alopecia) can be caused by elevated levels of free testosterone or androgen precursors. In women with normal serum levels of testosterone or androgen precursors, enhanced local conversion to testosterone, or to the more potent androgen dihydrotestosterone, may lead to increased androgen activity in the pilosebaceous unit. Large individual variations in the response to normal or elevated androgens suggests considerable differences in local androgen metabolism and androgen receptor-mediated activities, which may partly be related to genetic disposition. Androgens cause opposite effects on hair follicles in the scalp compared with the face and body, and there are large differences in the length of anagen phase. Androgens enhance sebum production and keratinization, prolong the growth phase of face and body hair, stimulate the transformation of vellus to terminal hair, and shorten the anagen phase of scalp hair. Estrogens may antagonize the androgen-induced actions on sebaceous glands and hair follicles. Treatment with oral contraceptives (OCs) reduces the production of androgens and androgen precursors and increases sex hormone-binding globulin, resulting in a decrease of free testosterone levels. According to type and dose, the estrogen and progestogen components of OCs may directly reduce the effect of androgens within sebaceous glands and hair follicles. Therefore, OCs with a predominant estrogen effect may improve mild to moderate forms of acne and seborrhea, hirsutism and androgenetic alopecia, in a time-dependent manner. In women who do not respond satisfactorily, treatment with OCs containing a progestogen with antiandrogenic activity is recommended. In many women with severe acne or hirsutism, a considerable increase in the local concentration of the antiandrogenic progestogen is required to reduce the androgenic interaction with the androgen receptor. For this therapy, an OC containing cyproterone acetate can be used. If necessary, the dose of cyproterone acetate can be increased in a stepwise manner. While androgenetic alopecia is best treated with a low-dose OC containing cyproterone acetate (optimal effect occurs after at least 12 months of therapy), severe acne and hirsutism are significantly improved after 6-12 months of regimens containing high doses of cyproterone acetate (25-100 mg/day). After termination of treatment the disorders may reappear, therefore treatment with suitable low-dose formulations is recommended to maintain the therapeutic effect.

Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women.

OBJECTIVE: To investigate the effects of tibolone on carbohydrate metabolism, and to compare these effects with those of a sequential regimen of conjugated equine estrogens and medrogestone. METHODS: This was an open-label, multicentre, comparative study. Seventy-two postmenopausal women were randomized to receive either tibolone 2.5 mg/day or conjugated equine estrogens 0.6 mg plus sequential medrogestone 5 mg (CEE/M) for six 28-day cycles. Carbohydrate metabolism was evaluated at baseline and after three and six cycles of treatment by an oral glucose tolerance test (OGTT). A blood sample was taken at 30, 60, 90 and 120 mm after glucose 75 mg dosing for determination of plasma glucose, insulin and connecting peptide (C-peptide) levels. RESULTS: The changes from baseline of glucose, insulin and C-peptide area-under-the-curve (AUC) values were not statistically significant after 3 and 6 months of tibolone or CEE/M treatment. There was a small transitory decrease in HbA(1C) after three cycles of treatment with tibolone. CONCLUSION: The effects of tibolone and CEE/M on carbohydrate metabolism were considered to have no clinical significance.

Effect of a low-dose contraceptive patch on efficacy, bleeding pattern, and safety: a 1-year, multicenter, open-label, uncontrolled study.

This Phase III, uncontrolled, open-label, multicenter study was conducted to investigate the contraceptive efficacy, bleeding pattern, and cycle control of a novel once-a-week contraceptive patch, delivering low-dose ethinyl estradiol (EE) and gestodene (GSD) at the same systemic exposure seen after oral administration of a combined oral contraceptive containing 0.02 mg EE/0.06 mg GSD. Participants were women aged 18 to 35 years, all of whom received the EE/GSD patch for 13 cycles each of 21 treatment days (one patch per week for 3 weeks) followed by a 7-day, patch-free interval. The primary efficacy variable was the occurrence of unintended pregnancies during the study period as assessed by life table analysis and the Pearl Index. Secondary efficacy variables were days with bleeding during four 90-day reference periods and during 1 treatment year, bleeding pattern, and cycle control. The Kaplan-Meier probability of contraceptive protection after 364 treatment days was 98.8% and the adjusted Pearl Index was 0.81. The percentage of participants with intracyclic bleeding/spotting decreased over time, from 11.4% to 6.8% in cycles 1 and 12, respectively. Almost all participants (range: 90.8%-97.6%) experienced withdrawal bleeding across the study period. Compliance was very high (mean: 97.9%; median: 100%). The most frequent adverse events were headache (9.5%) and application site reaction (8.5%); no clinically significant safety concerns were observed. Results suggest the EE/GSD patch is highly effective in preventing pregnancy. Menstrual bleeding pattern was favorable and within the ranges expected of a healthy female population. The patch was well tolerated and treatment compliance was high.