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.

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.

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.

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.

Treatment continuation and satisfaction in women using combined oral contraception with nomegestrol acetate and oestradiol: a multicentre, prospective cohort study (BOLERO).

OBJECTIVE: The aim of the study was to examine treatment continuation and satisfaction over 1 year among women receiving nomegestrol acetate (NOMAC)/oestradiol (E2) combined oral contraception (COC) in real-world clinical practice. METHODS: The 17ß-Estradiol and Nomegestrol Acetate (BOLERO) Study is an observational, non-interventional, prospective, multicentre cohort study of premenopausal women (aged 18-50 years) who received prescription NOMAC/E2 (2.5 mg/1.5 mg) for contraception during routine clinical practice. Assessments were carried out at enrolment and at 3, 6 and 12 months. Probability of treatment continuation through 12 months (primary outcome) was examined using Kaplan-Meier survival analysis. Secondary outcomes included treatment satisfaction, menstrual cycle-related symptoms, libido and adverse events (AEs). RESULTS: Of 298 enrolled women, 292 were evaluable. The probability of NOMAC/E2 continuation through 12 months was 73.7% (95% confidence interval [CI] 68.0%, 78.5%). Satisfaction with NOMAC/E2 increased from 56.9% (37/65) of women at initial evaluation to 89.2% (58/65) of women at 12 months. Physician ratings at 12 months showed satisfactory to very satisfactory in 84.0% (168/200) of women. Libido was not affected. Menstrual cycle-related symptoms significantly declined from enrolment (6.04 ± 4.32) to 3 months (3.25 ± 3.05) and 12 months (2.62 ± 2.74; p < .0001). Treatment-related AEs were reported by 38.7% (113/292) of women. CONCLUSION: The real-world experience of women receiving NOMAC/E2 indicated very good treatment continuation, high satisfaction and significantly improved menstrual cycle-related symptoms.

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.

Cryopreservation protocol for human biliary tree stem/progenitors, hepatic and pancreatic precursors.

Human biliary tree stem/progenitor cells (hBTSCs) are being used for cell therapies of patients with liver cirrhosis. A cryopreservation method was established to optimize sourcing of hBTSCs for these clinical programs and that comprises serum-free Kubota's Medium (KM) supplemented with 10% dimethyl sulfoxide (DMSO), 15% human serum albumin (HSA) and 0.1% hyaluronans. Cryopreserved versus freshly isolated hBTSCs were similar in vitro with respect to self-replication, stemness traits, and multipotency. They were able to differentiate to functional hepatocytes,cholangiocytes or pancreatic islets, yielding similar levels of secretion of albumin or of glucose-inducible levels of insulin. Cryopreserved versus freshly isolated hBTSCs were equally able to engraft into immunocompromised mice yielding cells with human-specific gene expression and human albumin levels in murine serum that were higher for cryopreserved than for freshly isolated hBTSCs. The successful cryopreservation of hBTSCs facilitates establishment of hBTSCs cell banking offering logistical advantages for clinical programs for treatment of liver diseases.

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.

Ovarian function during hormonal contraception assessed by endocrine and sonographic markers: a systematic review.

This systematic review focuses on the literature evidence for residual ovarian function during treatment with hormonal contraceptives. We reviewed all papers which assessed residual ovarian activity during hormonal contraceptive use, using endocrine markers such as serum anti-Müllerian hormone (AMH) concentrations, FSH, LH, oestradiol, progesterone and sonographic markers such as antral follicle count (AFC), ovarian volume and vascular indices. We considered every type (oestroprogestin or only progestin) and dosage of hormonal contraceptive and every mode of administration (oral, vaginal ring, implant, transdermal patch). We performed an electronic database search for papers published from 1 January 1990 until 30 November 2015 using PubMed and MEDLINE. We pre-selected 113 studies and judged 48 studies suitable for the review. Most studies showed that follicular development continues during treatment with hormonal contraceptives, and that during treatment there is a reduction in serum concentrations of FSH, LH and oestradiol, and also a reduction in endometrial thickness, ovarian volume and the number and size of antral follicles. The ovarian reserve parameters, namely AFC and ovarian volume, are lower among users than among non-users of hormonal contraception; regarding the effect of hormonal contraception on AMH, there are still controversies in the literature.

Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis.

BACKGROUND: Efforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis. METHODS: The cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced liver cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up. RESULTS: The resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up and the second patient maintained a stable improvement for 12 months. CONCLUSION: This report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials.

The Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of human biliary tree stem/progenitor cells.

BACKGROUND & AIMS: Human biliary tree stem/progenitor cells (hBTSCs) are multipotent epithelial stem cells, easily obtained from the biliary tree, with the potential for regenerative medicine in liver, biliary tree, and pancreas diseases. Recent reports indicate that human mesenchymal stem cells are able to modulate the T cell immune response. However, no information exists on the capabilities of hBTSCs to control the allogeneic response. The aims of this study were to evaluate FasL expression in hBTSCs, to study the in vitro interaction between hBTSCs and human lymphocytes, and the role of Fas/FasL modulation in inducing T cell apoptosis in hBTSCs/T cell co-cultures. METHODS: Fas and FasL expression were evaluated in situ and in vitro by immunofluorescence and western blotting. Co-cultures of hBTSCs with human leukocytes were used to analyze the influence of hBTSCs on lymphocytes activation and apoptosis. RESULTS: hBTSCs expressed HLA antigens and FasL in situ and in vitro. Western blot data demonstrated that hBTSCs constitutively expressed high levels of FasL that increased after co-culture with T cells. Confocal microscopy demonstrated that FasL expression was restricted to EpCAM(+)/LGR5(+) cells. FACS analysis of T cells co-cultured with hBTSCs indicated that hBTSCs were able to induce apoptosis in activated CD4(+) and CD8(+) T cell populations. Moreover, the Fas receptor appears to be more expressed in T cells co-cultured with hBTSCs than in resting T cells. CONCLUSIONS: Our data suggest that hBTSCs could modulate the T cell response through the production of FasL, which influences the lymphocyte Fas/FasL pathway by inducing "premature" apoptosis in CD4(+) and CD8(+) T cells.

Different bleeding patterns with the use of levonorgestrel intrauterine system: are they associated with changes in uterine artery blood flow?

OBJECTIVE: Evaluate if different bleeding patterns associated with the use of the levonorgestrel intrauterine system (LNG-IUS) are associated with different uterine and endometrial vascularization patterns, as evidenced by ultrasound power Doppler analysis. METHODOLOGY: A longitudinal study, with each subject acting as its own control was conducted between January 2010 and December 2012. Healthy volunteers with a history of heavy but cyclic and regular menstrual cycles were enrolled in the study. Ultrasonographic examination was performed before and after six months of LNG-IUS placement: uterine volume, endometrial thickness, and subendometrial and myometrial Doppler blood flow patterns have been evaluated. RESULTS: A total of 32 women were enrolled out of 186 initially screened. At six months of follow-up, all subjects showed a reduction in menstrual blood loss; for analysis, they were retrospectively divided into 3 groups: normal cycling women (Group I), amenorrheic women (Group II), and women with prolonged bleedings (Group III). Intergroup analysis documented a statistically significant difference in endometrial thickness among the three groups; in addition, mean pulsatility index (PI) and resistance index (RI) in the spiral arteries were significantly lower in Group I and Group III compared to Group II. This difference persisted also when comparing--within subjects of Group III--mean PI and RI mean values before and after insertion. CONCLUSIONS: The LNG-IUS not only altered endometrial thickness, but--in women with prolonged bleedings--also significantly changed uterine artery blood flow. Further studies are needed to confirm these results and enable gynecologists to properly counsel women, improving initial continuation rates.

Selective progesterone receptor modulators: an update.

INTRODUCTION: Several selective progesterone receptor modulators (SPRMs) show promise in several areas of medicine and this work has been summarized by us in 2008. AREAS COVERED: Since the publication of our reviews, several developments have taken place in the field of reproductive medicine. The first is emergency contraception (EC). Two SPRMs are clinically utilized today: mifepristone (MFP) and ulipristal acetate (UPA). MFP is available for EC in up to 120 h following unprotected intercourse. A dose of 10 mg is significantly more effective than levonorgestrel (LNG). In a metanalysis of the use of UPA versus LNG up to 72 h after unprotected intercourse, failure rates of 1.4 versus 2.2% were reported. The second is contraception. A daily dose of 2 mg MFP can block ovulation and several MFP regimens are being tested, including a vaginal ring releasing MFP. The third is the preoperative administration in women harboring leiomyomas, where clinical testing of several SPRM has shown that they can decrease uterine leiomyomas' size and substantially reduce uterine bleeding. SPRM can induce unusual, specific endometrial appearances. Many believe that these changes should not cause concern, but the issue remains controversial. EXPERT OPINION: SPRMs are very effective in EC and for the preoperative treatment of uterine leiomyomas.

Cholangiocarcinoma: increasing burden of classifications.

Cholangiocarcinoma (CCA) is a very heterogeneous cancer from any point of view, including epidemiology, risk factors, morphology, pathology, molecular pathology, modalities of growth and clinical features. Given this heterogeneity, a uniform classification respecting the epidemiologic, pathologic and clinical needs is currently lacking. In this manuscript we discussed the different proposed classifications of CCA in relation with recent advances in pathophysiology and biology of this cancer.

Selective progesterone receptor modulators 2: use in reproductive medicine.

BACKGROUND: Synthetic compounds can bind to progesterone receptors and these progesterone receptor ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. These substances have been classified as antiprogestins or as selective progesterone receptor modulators. OBJECTIVE: There are several hundred selective progesterone receptor modulators available, although only a dozen or so have been evaluated to any significant extent. The best-known selective progesterone receptor modulators are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex() (CDB 4124), ORG 33628 and ORG 31710. METHODS: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone, but also on those other selective progesterone receptor modulators for which data are available. RESULTS/CONCLUSIONS: Outside pregnancy, selective progesterone receptor modulators are used or have been tested clinically for a number of indications in reproductive medicine: as oral contraceptives, alone or in combination with a progestin, to improve cycle control in users of progestin-only contraceptives, as emergency contraceptives, for the medical treatment of uterine fibroids, in cases of endometriosis and premenstrual syndrome and to improve ovarian stimulation prior to in vitro fertilisation. In the authors' opinion, as of today, few applications outside pregnancy seem worthy of large-scale use: emergency contraception and long-term medical management of uterine fibroids and possibly of endometriosis.

Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry.

BACKGROUND: A number of synthetic steroids are capable of modulating progesterone receptors with a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. The best known of these are mifepristone (RU 486), asoprisnil (J 867), onapristone (ZK 98299), ulipristal (CDB 2914), Proellex() (CDB 4124), ORG 33628 and ORG 31710. OBJECTIVE: Outside reproduction selective modulators of progesterone receptors have been under investigation for a large variety of indications, for example in oncology as adjuvants in breast, cervical, endometrial, ovarian and prostate cancer, as well as inoperable meningioma and leiomyosarcoma. In addition, they have been used as antiglucocorticoids. It is therefore useful to review the results obtained in these conditions. METHODS: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone but also on those other selective modulators of progesterone receptors for which data are available. RESULTS/CONCLUSIONS: In preliminary studies selective modulators of progesterone receptors had some activity on a number of neoplasias. Their antiglucocorticoid activity has been tested with some success in Cushing's syndrome, several psychiatric conditions (e.g., mood disorders and Alzheimer's disease) and acute renal failure. Finally they are being used in a gene regulator system.

Emergency contraception: a review.

Emergency contraception (EC), also known as 'the morning after pill', or post-coital contraception, is a modality of preventing the establishment of a pregnancy after unprotected intercourse. Both a hormonal and an intrauterine form are available. Modern hormonal EC, with low side effects, was first proposed by Yuzpe in 1974. More recently, a new regimen, consisting of levonorgestrel administered alone, was introduced and found in clinical trials to be more effective (if taken as early as possible), and associated with less side effects than the Yuzpe regimen, which it has gradually replaced. The WHO developed another regimen based on the use of the selective progesterone receptor modulator (antiprogestin) mifepristone and conducted trials with different dosages. Intrauterine EC was first proposed by Lippes in 1976. It has the advantage of being applicable for almost a week and the disadvantage of a greater complexity. In addition, this modality is solely interceptive, acting by preventing implantation. Pregnancy rates reported following EC using an intrauterine device with more than 300 mm2 of copper are consistently low (0.1-0.2%).

Hormonal contraception: present and future.

The original form of hormonal contraception ("the Pill") has developed into a variety of modalities administered through different routes: oral, intramuscular, subcutaneous, transdermal, intrauterine or intravaginal, and intranasal (abandoned). At present, two separate methods of hormonal contraception exist; one is used to prevent fertilization and the other to prevent pregnancy. From a pharmacological point of view, hormonal methods utilize either a combination of estrogen and progestin or progestin alone. Today all combined methods contain ethynylestradiol, and over the years there has been a substantial reduction in its dosage from almost 80 microg to as low as 15 microg. On the other hand, a variety of progestins are currently utilized that belong to two main chemical families: derivatives of progesterone and derivatives of 19-nortestosterone or gonane. These compounds, developed over a period of 50 years, can be distinguished in four successive "generations". Recent developments include new oral regimens intended to change the 7-day medication-free interval and new commercial preparations; the latter utilize the progestins drospirenone and dienogest. In addition, an oral contraceptive containing chlormadinone has also been marketed. Besides the oral route, contraceptive systems exist or are under development that employ the intramuscular, transdermal and intravaginal routes; they deliver both an estrogen and a progestin. Several patches and vaginal rings are also marketed. A variety of long-acting methods delivering only a progestin are also available. They use the subcutaneous route or are released from an intrauterine system, both of which provide optimal contraceptive protection and, depending on the system, can last up to 5 years (and probably more). Finally, progestin-releasing vaginal rings are under investigation. The second type of hormonal contraception, called "emergency contraception", utilizes progestins and antiprogestins and to be effective should be taken as soon as possible after unprotected intercourse.

Contraception today.

Modern contraceptive methods represent more than a technical advance: they are the instrument of a true social revolution-the "first reproductive revolution" in the history of humanity, an achievement of the second part of the 20th century, when modern, effective methods became available. Today a great diversity of techniques have been made available and-thanks to them, fertility rates have decreased from 5.1 in 1950 to 3.7 in 1990. As a consequence, the growth of human population that had more than tripled, from 1.8 to more than 6 billion in just one century, is today being brought under control. At the turn of the millennium, all over the world, more than 600 million married women are using contraception, with nearly 500 million in developing countries. Among married women, contraceptive use rose in all but two developing countries surveyed more than once since 1990. Among unmarried, sexually active women, it grew in 21 of 25 countries recently surveyed. Hormonal contraception, the best known method, first made available as a daily pill, can today be administered through seven different routes: intramuscularly, intranasally, intrauterus, intravaginally, orally, subcutaneously, and transdermally. In the field of oral contraception, new strategies include further dose reduction, the synthesis of new active molecules, and new administration schedules. A new minipill (progestin-only preparation) containing desogestrel has been recently marketed in a number of countries and is capable of consistently inhibiting ovulation in most women. New contraceptive rings to be inserted in the vagina offer a novel approach by providing a sustained release of steroids and low failure rates. The transdermal route for delivering contraceptive steroids is now established via a contraceptive patch, a spray, or a gel. The intramuscular route has also seen new products with the marketing of improved monthly injectable preparations containing an estrogen and a progestin. After the first device capable of delivering progesterone directly into the uterus was withdrawn, a new system releasing locally 20 microg evonorgestrel is today marketed in a majority of countries with excellent contraceptive and therapeutic performance. Finally, several subcutaneously implanted systems have been developed: contraceptive "rods," where the polymeric matrix is mixed with the steroid and "capsules" made of a hollow polymer tube filled with free steroid crystals. New advances have also been made in nonhormonal intrauterine contraception with the development of "frameless" devices. The HIV/AIDS pandemic forced policy makers to look for ways to protect young people from sexually transmitted diseases as well as from untimely pregnancies. This led to the development of the so-called dual protection method, involving the use of a physical barrier (condom) as well as that of a second, highly effective contraceptive method. More complex is the situation with antifertility vaccines, still at a preliminary stage of development and unlikely to be in widespread use for years to come. Last, but not least, work is in progress to provide effective emergency contraception after an unprotected intercourse. Very promising in this area is the use of selective progesterone receptor modulators (antiprogestins).