Attitudes of women and pharmacists on the opportunity to obtain a progestogen-only pill over the counter - Italian outcomes.

PURPOSE: Scrutinizing, among potential providers and users, the perceived claim and interest for over the counter (OTC) accessibility of a progestogen-only pill (POP). METHODS: Cross-sectional, descriptive study based on an online survey of 1000 women and 100 pharmacists in Italy, part of a larger sample including Germany and Spain. RESULTS: Hormonal contraceptive methods are used by 35%; 5% of women reported currently not using contraception, 40% using a barrier method, and 20% a method considered less effective than male condoms (including 16% withdrawal and 4% natural methods and fertility/contraceptive applications). Almost 80% of women felt knowledgeable about the different contraceptive method, but about 1/3 had experienced difficulty accessing their oral contraceptive (OC) in the past two years. Women reacted positively to the proposition of an OTC-POP and 85% agreed that they would discuss the decision to buy it with their doctor; 75% reported they would continue to see their doctor for other reproductive health issues, including screening. The most frequent barrier is cost (reported by 25-33% of women) followed by long waiting times for doctor appointments and lack of personal time to schedule an appointment.Pharmacists (66%) would be likely/fairly likely to recommend the POP after appropriate training, agreeing that the benefits of an OTC-POP included improved access for women, saving them time and giving them more independence. CONCLUSIONS: Potential users of contraception in Italy have a positive attitude toward OTC-POP, with doctors continuing to have a relevant role. Following training, pharmacists are also positive.

Overcoming barriers to oral contraception in Italy an expert opinion to empower women.

Oral contraceptives are among the most commonly used contraceptive methods. However, Italian women underused reliable hormonal contraceptives as compared with other European women. There is a need to streamline access to oral contraception, with expected benefits on emotional well-being of women and potential savings for health system in Italy. Indeed, women can only access to oral contraceptives through mandatory medical prescription. This is one of the most important barrier experienced by women. We hereby provide an expert opinion on the potential reclassification, extending pharmacy services to include responsible and appropriate use of POP, as an opportunity also in Italy to increase the use of safe and effective contraceptive methods.

Attitudes towards menstruation: what women want? An Italian National Survey.

OBJECTIVE: Many women experience negative feelings during menstrual bleeding. Aim of the study was to evaluate the attitudes of Italian women towards menstrual bleeding, their desire to reduce its frequency and knowledge of the existence of methods capable of achieving such an objective. METHODS: An internet-based anonymous questionnaire has been sent to women willing to fill it in through different social media (Instagram, WhatsApp, Facebook, Twitter). The survey evaluated, objective parameters such as number of pads, use of painkillers, duration of period and pain intensity. Judgement towards period and knowledge about methods to reduce frequency and amount of menstrual flow were analysed. RESULT: 1072 Women aged 18 - 40 years, answered the survey. The level of education of responders was high, with 61.7% having a university degree. 27.5% of respondents viewed positively the occurrence of a menstrual period. Ideal frequency of menstrual cycles was considered 3 months and the perfect duration was considered to be 3 days. Half of the respondents ignored the existence of methods to suppress menstruation or reduce its frequency. 52% of participants stated that they would not use a contraceptive method because they considered it not 'natural'. CONCLUSIONS: In our sample, in spite of the discomfort reported by half of the women interviewed, menstruation was considered positively by one fourth as because confirm their fertility. The majority of women did consider bleeding every month a healthy, but they preferred a three-monthly frequency. Knowledge of contraceptive methods capable of reducing the frequency of menstrual bleeding was scarce.

The use of different doses levonorgestrel-releasing intrauterine system (LNG-IUS): real-world data from a multicenter Italian study.

PURPOSE: Current research fails to adequately inform about the differential use of available levonorgestrel-releasing intrauterine systems (LNG-IUSs) in real life. Aim of our study was to compare the characteristics, satisfaction, continuation rates, and adverse effects between users of the high-dose LNG-IUS (52 mg) and of the low dose LNG-IUS (13.5 mg and 19.5 mg). MATERIALS AND METHODS: A prospective cohort study was performed in two Services for Family Planning in normal menstruating women with the inclusion of all new prescriptions of LNG-IUS for contraception. Women were followed for a mean of 9.1 ± 2.6 months after placement. RESULTS: 109 women (mean age of 39.8 ± 8.7 years old) were included, 69.7% using a high dose LNG-IUS and 30.3% using a low dose LNG-IUS. Women with a low dose LNG-IUS were significantly younger, thinner, more nulliparous, with fewer vaginal deliveries and C-sections, with a lower menstrual flow length and with more previous use of short-acting reversible contraceptives (p < 0.05). LNG-IUS continuation was similar and very high at the last follow-up: 100 vs. 94.7% in the low and high dose LNG-IUS groups, respectively (p = 0.18). Satisfaction with treatment at the end of the study was similar between different LNG-IUS doses (p = 0.85), with 78.9% being satisfied/very satisfied. Bleeding patterns were significantly different between the two LNG-IUS doses (p < 0.0001). Diagnosis of dysfunctional cysts was more frequent in women with high dose compared to low dose LNG-IUS (22.2 vs. 12.1%), albeit not significantly. CONCLUSIONS: We have shown a clear differential use of available LNG-IUS in clinical practice, both as baseline characteristics and as different outcomes, primarily for bleeding patterns. However, all these systems were associated with a very high rate of satisfaction and continuation.

The views of women and pharmacists on the desirability of a progestogen-only pill over the counter. Results of a survey in Germany, Italy and Spain.

PURPOSE: To explore the perceived need and enthusiasm for over the counter (OTC) progestogen-only pills (POP). MATERIALS AND METHODS: A web-based survey of 1000 sexually active women (16-45) and 100 pharmacists in Germany, Italy and Spain. RESULTS: Despite not wanting to conceive, 5-6% of women in each country were not using contraception and 8-20% were using methods less effective than condoms. At least 74% of respondents felt knowledgeable about the different contraceptives available but at least 1/3 had experienced difficulty accessing oral contraceptive (OCs) in the past two years. The cost of contraceptives, the need to see a doctor and long waits for appointments were cited as barriers for not using OCs. The majority agreed they would discuss with their doctor the decision to buy the POP, consult about side effects and other reproductive health issues. Over 2/3 of pharmacists in each country would be very, or fairly, likely to recommend the POP, agreeing that the benefits included improved access for women, and offered them more independence. CONCLUSIONS: Asked directly, women in Germany, Spain and Italy currently using contraception are positive about a POP OTC. Pharmacists are also positive, with the overwhelming majority in favour of providing POPs.

An observational study of adherence to combined oral contraceptive regimens.

OBJECTIVE: To analyze adherence to an oral contraceptive (OC) regimen and correlate results to participants' socio-demographic and behavioral characteristics. METHODS: Women were prospectively enrolled and followed for 6 months. At enrollment, subjects were given a card for recording daily pill intake; its completion was checked at 6 months when women completed a self-administered questionnaire. RESULTS: Out of 755 eligible subjects, 704 agreed to participate; 402 women completed 6 months of recording of use of an OC and properly filled the questionnaire. Good adherence was reported by 64% of participants; 20.9% missed one pill and 14.9% missed more than one pill. Mean number of missed pills per subject was 0.59 and mean number of pills delayed for less than 24 h was 1.18. Best adherence to a COC regimen was associated with evening time intake (p = 0.0019). No statistically significant associations of adherence with socio-demographic characteristics were found. Age was only marginally associated with having missed at least one pill. CONCLUSION: In the present study, a lower number of missed pills were observed than previously reported, but the proportion of missed pills was similar. No association with specific subject characteristics that could serve as markers of increased risk of nonadherence was found.

Emergency contraception: a survey of 1773 women.

OBJECTIVES: The aim of the study was to retrieve data on the characteristics and profile of women attending an emergency service (ES) to receive a prescription (mandatory until May 2015) for emergency contraception (EC). METHODS: In a retrospective study the following data were collected for all women requesting EC between January 2014 and June 2015: demographic characteristics, time between unprotected sexual intercourse (USI) and arrival at the ES, time between the last menstrual period and the USI, and type of EC prescribed. In a prospective study starting January 2015, a questionnaire was administered requesting the following information: reasons for requiring EC, previous EC use, source of knowledge about EC, prior contraception and age at first intercourse. RESULTS: During the whole study period, 1773 women requested EC: their mean age was 26.0 years; 78.5% were Italian; 91.5% were unmarried; 55.2% were still studying and 51.9% had high school education; 61.2% reached the ES within 12 h of the USI; and 42.4% had a USI during days 9-16 of their menstrual cycle. Levonorgestrel was prescribed in 81.4% of women and ulipristal acetate in 17.7%. In the prospective part of the study (382 women), the majority (57.9%) requested EC for condom rupture; 49.5% reported previous use of EC; and 41.6% received information on the subject through friends. The vast majority (83.8%) reported prior use of contraception; in 25.4% the reason for not using it was the absence of a relationship. CONCLUSION: An exact profile of women requesting EC can help women in their choice of permanent contraception, and help clinicians in counselling women on appropriate contraception.

Second-trimester induced abortions in two tertiary centres in Rome.

OBJECTIVE: Demand for second-trimester induced abortions (STIAs) increases in Italy. For these procedures, prostaglandins alone were used until 2010, when mifepristone became available. The present study compares the two modalities, and investigates the reasons for STIAs. METHODS: The records of all such procedures performed at the Department of Gynaecology, Obstetrics and Urology of the 'Sapienza' University (Rome), between January 2004 and December 2012, and of all those done at the 'San Filippo' Hospital (Rome), between January 2010 and December 2012, were analysed. Data gathered included women's age, obstetric history, reasons for requesting the STIA, gestational age, mode of intervention, and complications if any. RESULTS: During the study period, 353 women requested a STIA. Karyotype or genetic anomalies were the reason for the request in 187 cases (53%), while structural anomalies, both single and multiple, were given as the reason in 158 (45%). In most cases, these anomalies were assessed by ultrasound scan. CONCLUSION: Few studies have investigated reasons for requesting STIAs. Of all chromosome abnormalities diagnosed in this study, trisomy 21 was the most common (59%) and it was the most frequent reason for requesting pregnancy termination.

The effect of different contraceptive methods on the vaginal microbiome.

Introduction: Following a historical overview, the effect of different contraceptive methods on vaginal microbiome has been reviewed and summarized.Areas covered: Effects of combined hormonal contraceptives (oral or vaginal) and of progestin only (injectable and implantable), intrauterine devices/systems (copper- or levonorgestrel-releasing), on vaginal microbiome. In addition, mention is made of vaginal rings releasing antiviral drugs and lactic acid.Expert opinion: The vaginal microbiota (VM) is unique in that it is normally dominated by Lactobacillus species providing a degree of protection against infections; this however may vary, depending on the species and strains of Lactobacillus. Bacterial Vaginosis represents the most common dysbiosis of the VM and its prevalence can be influenced by use of contraception. Available evidence indicates that, under the influence of oral or systemically administered female sex hormones, there is apromotion of vaginal eubiosis, with aprevalence of ahealthy VM in which Lactobacilli predominate.

Fate of fertilized human oocytes.

Establishing the proportion of fertilized oocytes and early human embryos that proceed to term may help policy makers in their evaluation of when the life of a new human individual begins and in determining the nature of protection to be accorded to it. The rate of spontaneous abortions, although increasing with age, overall does not exceed 15%. However, abortion rates refer only to 'clinical pregnancy', whereas early embryonic loss is more common than generally believed. Evidence of such wastage comes from many sources. Human fecundity rarely exceeds 35% and may be decreasing due to deterioration in semen quality. Embryological studies show that 50% of randomly recovered preimplantation embryos have severe anomalies. The study of sensitive markers of pregnancy, such as human chorionic gonadotrophin, indicates early embryo wastage in the order of 50%. Pregnancy wastage may be a function of the time lapse between ovulation and implantation as the implantation window extends between menstrual cycle days 20 and 24. Finally, data obtained with natural IVF cycles also indicate major losses, with an overall pregnancy rate of 7.2% per cycle and 15.8% per transfer. These data, however, are biased by a high cancellation rate and low oocyte retrieval in natural IVF cycles.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 4. Effects on uterine and cervical epithelia.

Introduction: Steroid hormones are responsible for specific changes in the endometrium during the menstrual cycle, when they are sequentially secreted and, because of this, in the early days sequential combined oral contraceptive regimens were utilized. The same basic concept has been utilized with multi-phasic regimens, in order to produce endometrial pictures mimicking the normal cycle.Areas covered: The Endometrial effects of progestins and estrogens; combined monophasic high- (50 µg), medium- (30 µg), low- (20 µg), ultralow- (15 µg) estrogen content; sequential regimens; multiphasic combinations; treatment schedules.Cervical effects of combined high-dose and sequential combinations, including evidence for an increase in malignant lesions.Expert opinion: Overall, combined oral contraceptives (COCs) inhibit normal proliferative changes and the endometrium becomes thin, narrow, with widely spaced glands and pre-decidual changes in the stroma. During the first few cycles the progestin induces a coexistence of proliferative and secretory features; with time, the picture changes because the progestin induces a down-regulation of estrogen receptors, resulting in tortuous glands similar to those in the secretory phase, but characterized by a quiescent, atrophic glandular epithelium.In the cervical epithelium, under the influence of high-dose COCs, endocervical glands became hypersecretory and in some instances, distinctive type of atypical polypoid endocervical hyperplasia is found.

Effects of progestin-only contraceptives on the endometrium.

INTRODUCTION: The contraceptive activity of synthetic progestins is mediated through three basic mechanisms: (a) An anti-gonadotrophic action leading to the inhibition of ovulation; (b) Changes in cervical mucus characteristics that inhibit sperm penetration and (c) desynchronization of the endometrial picture necessary for implantation. AREAS COVERED: Mechanisms involved in the progestin-induced endometrium desynchronization are individually reviewed for each of the routes of administration and, whenever possible, by individual members of the various families of synthetic progestin derivatives. EXPERT OPINION: For contraceptive purposes, progestins are today administered through several routes: orally, as injections, subdermally and via the vagina or the uterine cavity. Given this variety of modalities, their effects may differ, depending on the route of administration, concentration reached at the level of the endometrium and the duration of use. These are characterized by inactivation of the endometrium. Progestin-only contraception provides a safe and effective control of fertility regulation, although, they are associated with the problem of endometrial break through bleeding that may lead to discontinuation. Unfortunately, in spite of a major research effort over two decades, there is not, as yet, an established long-term intervention available to manage bleeding irregularities, making mandatory a deeper understanding of the mechanisms involved is required.

Uterine fibroids: an update on current and emerging medical treatment options.

Uterine fibroids are the most common gynecological disorder, classically requiring surgery when symptomatic. Although attempts at finding a nonsurgical cure date back to centuries, it is only around the middle of the last century that serious attempts at a medical treatment were carried out. Initially, both progestins and estrogen-progestin combinations have been utilized, although proof of their usefulness is lacking. A major step forward was achieved when peptide analogs of the GnRH were introduced, first those with superagonist properties and subsequently those acting as antagonists. Initially, the latter produced side effects preventing their routine utilization; eventually, this problem was overcome following the synthesis of cetrorelix. Because both types of analogs produce hypoestrogenism, their use is limited to a maximum of 6 months and, for this reason, today they are utilized as an adjuvant treatment before surgery with overall good results. Over the last decade, new, nonpeptidic, orally active GnRH-receptor blockers have also been synthesized. One of them, Elagolix, is in the early stages of testing in women with fibroids. Another fundamental development has been the utilization of the so-called selective progesterone receptor modulators, sometimes referred to as "antiprogestins". The first such compound to be applied to the long-term treatment of fibroids was Mifepristone; today, this compound is mostly used outside of Western Countries, where the substance of choice is Ulipristal acetate. Large clinical trials have proven the effectiveness of Ulipristal in the long-term medical therapy of fibroids, although some caution must be exercised because of the rare occurrence of liver complications. All selective progesterone receptor modulators produce unique endometrial changes that are today considered benign, reversible, and without negative consequences. In conclusion, long-term medical treatment of fibroids seems possible today, especially in premenopausal women.

Nexplanon Subdermal Implant: Assessment of Sexual Profile, Metabolism, and Bleeding in a Cohort of Italian Women.

OBJECTIVES: To evaluate the impact on metabolism, bleeding, and sexual function of Nexplanon, a subdermal implant. STUDY DESIGN: We recruited women (n=101) receiving the Nexplanon implant at two university centers in Italy between 2011 and 2016 into this prospective, observational, multicenter research trial. Participants completed the Interview for Ratings of Sexual Function (IRSF) and the Female Sexual Function Index (FSFI) questionnaires before and 3 and 6 months after the implant was inserted. In addition, all blood parameters were assessed at these visits. All women were given a menstrual diary card and a pictorial blood assessment chart to record daily any vaginal bleeding. RESULTS: The studied metabolic parameters remained in the normal range, showing no alarming modifications: minimal statistical reductions (in aspartate aminotransferase, alanine aminotransferase, total cholesterol, triglycerides, and activated partial thromboplastin time) and increases (in glucose and prothrombin activity) were observed. Changes in IRSF score over 6 months showed a significant increase in pleasure, personal initiative, orgasm, intensity of orgasm, and satisfaction, and a significant decrease in anxiety and discomfort. Mean Body Mass Index decreased, and the weekly frequency of sexual intercourse increased. CONCLUSIONS: Nexplanon showed not only a lower metabolic and bleeding impact, but also important positive effects on sexual function. It expands the range of possibilities for women, 38 and couples, in the modern concepts of sexual and reproductive wellbeing.

Contraceptive devices: subcutaneous delivery systems.

Ever since natural sex hormones have been identified, their structure defined and their synthesis achieved, it became clear that their circulating half-life was too short to allow use in therapy. One of the modalities most thoroughly investigated to prolong their duration of action is to embed them in a polymeric matrix and administer them subcutaneously. Research and development activities of devices to be inserted under the skin have focused upon two modalities: the first utilizes the so-called nonbiodegradable devices, in which the matrix is fixed and the drug is made available through diffusion. In the second, biodegradable devices, the matrix dissolves during the process and both the active compound and the matrix components reach the circulation. Although a number of biodegradable systems have been investigated in the form of polymeric rod or micropellets, so far no system has reached the marketplace. Several matrices have been evaluated: poly(ortho esters), (polylactic-polyglycolic acid)co-polymers, poly-(epsilon-caprolactone). In the case of nonbiodegradable systems, several have been in widespread use for years. The first such system, Norplant 1, consists of six capsules delivering levonorgestrel and lasts a minimum of 5 years; the second, called Norplant 2 (Jadelle), consists of only two rods delivering the same amount of steroid of the first system, for the same duration of time. A third system already on the market is made up of a single rod releasing etonogestrel, the active metabolite of desogestrel, with duration of action of 3 years. Additional systems are still at the premarket stage. Subcutaneous implants have several obvious advantages, first and foremost their duration of action that can extend to at least 5 years, making them especially suitable for family-planning programs in developing countries; in addition, they are user- independent, again a positive feature in certain settings. Among the disadvantages, is a relatively complex insertion procedure that, for older systems, required ad hoc trained personnel and a small incision, clearly a disincentive. Newer devices, however, require a much simpler insertion procedure. Extracting systems is also complex and if a woman is lost to follow-up, implants will remain in the subcutaneous tissue forever.

Contraceptive devices: intravaginal and intrauterine delivery systems.

Substances with an antifertility activity can be delivered directly into the vagina and the uterus. Indeed, it has been known for decades that the vaginal mucosa is an excellent way through which to deliver a number of compounds to the general circulation. Research and development efforts have concentrated on rings delivering only progestins, or both an estrogen and a progestin. The only combined ring marketed so far releases 15 microg ethynyl estradiol and 120 microg etonogestrel, and has a failure rate between one and two per 100 women-years of use. It has a preset duration of action of 1 month, has to be inserted before day 5 of the cycle, irrespective of the presence of menstrual flow, and withdrawn after 21 days, thereby allowing proper cycle control. Among rings releasing only a progestin, one device releasing progesterone has been marketed; all others are still under development. Unlike other long-term methods, vaginal rings do not require the involvement of a healthcare professional and can be inserted and removed by the user. The first attempt at achieving contraception by inserting a device in the uterus is 100 years old. Half a century later, medicated intrauterine systems were investigated; they are superior to inert devices and today a number of active principles, such as copper and progestogens, have been incorporated and tested when released from an intrauterine device (IUD). Copper-releasing devices last more than 10 years, with cumulative pregnancy rates of between approximately 5 and 3, and cumulative expulsion rates between approximately 12 and 8. With all IUDs, bleeding and pain are the most common reasons for a request to withdraw a device. There is agreement that fertility after removal of a copper-IUD is not impaired. Finally, the overall risk of ectopic pregnancy is reduced in IUD users, compared with using no contraception. The first progestogen-releasing system contained progesterone, had 1-year duration of action and was marketed some 30 years ago; unfortunately, it was shown that failure caused an increase of extrauterine pregnancies. This potentially dangerous effect eventually led to the withdrawal of the device from the market. In the meantime, a device releasing the synthetic progestin levonorgestrel was being developed and has now been successfully marketed; it lasts for a minimum of 5 years and, although absorbed systemically, cyclic function is maintained. The system is one of the most effective methods of contraception available today: large clinical studies indicate a Pearl index of 0.1 per 100 woman-years. Although a postfertilization effect cannot be excluded, in a majority of cases, intrauterine systems act as true contraceptives, preventing fertilization.

Pharmacodynamics of combined estrogen-progestin oral contraceptives 3. Inhibition of ovulation.

INTRODUCTION: Following a historical overview, the ovulation-inhibiting effect of various orally administered estrogen-progestin combinations (combined oral contraceptives [COCs]) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Inhibition of ovulation with progestins alone; estrogens alone; various progestins in combination with ethinyl estradiol; various progestins in combination with natural estrogens (estradiol, estradiol valerate, and estetrol). Expert commentary: The original idea to achieve ovulation blockage through the administration of steroid hormones involved the use a progestogen (both progesterone and its synthetic homologous). The ability of a progestin to inhibit ovulation depends on the type of compound and on its dosage and a difference of more than 20-fold in activity exists between compounds utilized today in COCs. Initially, the estrogenic component was present only because it contaminated the first progestin utilized. It was soon found that an estrogen is necessary for proper cycle control. It was also found that the estrogen acts synergistically in inhibiting ovulation. For almost half a century, most COCs contained ethinyl estradiol. Today, also natural estrogens are being employed. Inhibition of ovulation was complete with all early high dose preparations. Decreasing dosage allowed some ovarian activity to occur, occasionally leading to a mature follicle. Even in this situation, defective corpus luteum formation assured contraceptive protection.

Menopause and hormone replacement therapy: the 2017 Recommendations of the Italian Menopause Society.

Over the last decade, the risk benefits ratio of hormone replacement therapy (HRT) has been reevaluated mainly in tens of cardiovascular risk. Present Consensus Statement is largely inspired by the Global Consensus on Menopausal Hormone Therapy in 2013 and 2016 by leading global menopause societies (The American Society for Reproductive Medicine, The Asia Pacific Menopause Federation, The Endocrine Society, The European Menopause and Andropause Society, The International Menopause Society, The International Osteoporosis Foundation and The North American Menopause Society). The aim of these recommendations is to provide a simple and updated reference on postmenopausal HRT. The term HRT typically includes estrogen replacement therapy (ERT) and estrogen-progestogen therapy (EPT). EPT can be sequential, when progestogen is added to ERT for 10-14 days a month, or continuous combined when progestogen is administered continuously every day along with a fixed amount of estrogen, In the everyday language, HRT includes also tibolone and the tissue-selective estrogen complex.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis.

INTRODUCTION: The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 1. Effects on metabolism.

INTRODUCTION: The risk-benefit profile of any pharmacologic agent must be evaluated against risks connected with the events to be avoided. This is especially true in the case of hormonal contraception, not intended to combat a disease. Over the six decades during which their use has progressively expanded, the risk-benefit profile of combined oral contraceptives (COC) has substantially changed, with new combinations, dosages and mode of administration appearing on the market. Area covered: In a series of articles, recent information on the complex issue of COC risks and benefits will be reviewed in the hope of providing an updated picture. The present article reviews metabolic changes occurring during use of modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), often compared to classic compounds, such as levonorgestrel. Three categories of metabolic effects in healthy women are detailed: on carbohydrates, lipid and bone mineral content. Expert commentary: Overall, the picture is reassuring: the new generations of progestins are basically devoid of androgenic, estrogenic or glucocorticoid related side-effects. This should result in an improved safety profile, although past history teaches us that that large comparative and surveillance studies are required before firm conclusions can be drawn. At any rate, available evidence indicates that metabolic effects of third and fourth generation progestins, especially when they are combined with natural estrogens, are minimal and, if used in healthy women, should not cause concern.