Mechanism of Action of Ulipristal Acetate for Emergency Contraception: A Systematic Review

SUMMARYUlipristal acetate (UPA) is now recommended as first choice hormonal Emergency Contraception (EC), due to its higher efficacy and similar safety compared to Levonogestrel - EC. Even though all trials demonstrated that the first mechanism of action is inhibition of ovulation, some authors still postulate that a post fertilization effect is also possible, raising the alert on medication and fostering the ethical debate.A Medline database search was performed in order to find recent articles related to UPA’s effects on ovulation, on fallopian tube and on endometrium. We also analyzed the effects on sperm function and pregnancy. All studies conclude that UPA is effective in inhibition of ovulation even when administered shortly before LH peak. The effects on fallopian tube are unclear: according to some authors UPA inhibits ciliar beat through an agonistic effect on progesterone receptors, according to others it antagonizes the progesterone-induced ciliar beat decrease. Concerning the action on endometrium and on embryo implantation most of the studies concluded that low dose UPA used for EC has no significant effect on the decrease of endometrial thickness and on embryo’s attachment, but these results are still matter of debate. Finally recent evidence suggests that UPA modulates human sperm functions while it has no effect on established pregnancy. To date the majority of the evidence concur in excluding a post-fertilization effect of UPA, even though more studies are needed to clarify its mechanism of action

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

Effetti di un sistema intrauterino liberante levororgestrel (lgn-ius) sui caratteri del ciclo mestruale, la qualità della vita e la sessualità

Scopo: Scopo dello studio è stato di valutare l’azione di un dispositivo intrauterino liberante levonorgestrel (LNG-IUS) sui caratteri del ciclo mestruale, la qualità della vita e la sessualità Materiali e metodi: Per lo studio sono state arruolate, presso il Servizio Speciale di Pianificazione Familiare del Dipartimento di Ginecologica dell'Università "La Sapienza" di Roma, 128 donne, volontarie, tra i 26 e 49 anni (media 38,5), che richiedevano contraccezione intrauterina e soddisfacevano i criteri di inclusione nello studio. Al momento del reclutamento, queste donne, sono state seguite secondo un protocollo che prevedeva, una visita ginecologica in cui venivano valutate le caratteristiche demografiche, le caratteristiche fisiche generali, la storia ostetrica, il tipo di contraccettivo usato in precedenza ed il tipo di ciclo mestruale delle singole pazienti dando particolare importanza alla durata ed alla quantità del flusso, un pap-test ed un esame ecografico basale, quindi ripetizione della visita e dell'esame ecografico dopo 1, 3, 6, 12 e 36 mesi; ad ognuna è stato chiesto di compilare un diario mestruale dove segnalare le caratteristiche del ciclo ed eventuali effetti collaterali. Al fine di valutare gli effetti sulla qualità della vita e sulla sessualità, a tutte le donne incluse nello studio sono stati assegnati al momento del reclutamento ed a 6 mesi dall’inserzione, ed in caso di drop-out dallo studio i questionari EQ-5D ed il Female Sexual Function Index (FSFI). Risultati: Nel campione preso in esame prevalgono le donne pluripare (86.7%) su quelle nullipare (13,3%). Durante i 4608 donne/mese di osservazione non si è verificata nessuna gravidanza. La perdita ematica mestruale si è ridotta in tutte le pazienti sia in termini di quantità che di durata. Nella maggior parte dei casi (91.0%) lo spotting si è risolto entro 6 mesi, mentre nel 29,5% delle donne nei primi 6 cicli post-inserimento. Cinque soggetti hanno richiesto la rimozione anticipata del sistema intrauterino: due per desiderio di gravidanza che in entrambi i casi si è verificata entro sei mesi dall’estrazione, mentre altre 3 donne, nonostante una precedente condizione di menorragia, hanno richiesto la rimozione anticipata poiché non potevano psicologicamente tollerare l’amenorrea. Non sono stati osservati effetti collaterali, correlati all’uso di un progestinico come aumento di peso o acne mentre il 35% delle donne ha riportato tensione mammaria durante i primi 6 mesi d’uso del sistema intrauterino. Al controllo ecografico a tre mesi si è osservata la presenza in 3 donne, di cisti ovariche disfunzionali, con un diametro fino a 5 cm, che si sono risolte spontaneamente entro 60 giorni. I dati del questionario EQ-5D mostrano un significativo miglioramento dello stato di benessere complessivo da una media di 0,70 al reclutamento a 0,10 a 6 mesi (p=0,02) I dati relativi al FSFI, pur non mostrando una significativa differenza tra le due valutazioni, presentano una considerevole variabilità interindividuale per quanto riguarda il desiderio sessuale. Le sole differenze significative osservate riguardano i domini del desiderio sessuale e del dolore. Conclusione: Lo LNG-IUS ha mostrato di essere un sistema contraccettivo sicuro ed efficace, come dimostrato dall’assenza di gravidanze durante il periodo di osservazione, particolarmente indicato in quelle donne che presentano menorragia. Si è osservato un significativo miglioramento della qualità della vita in seguito all’inserzione del dispositivo, come riportato anche in altri studi. Per quanto riguarda la sessualità, i risultati da noi osservati sono simili a quelli riportati da altri studi che però prendevano in considerazione l’uso di contraccettivi orali combinati, con un numero simile di donne che presentano modificazioni negative o positive. Contrariamente a quanto da noi osservato studi comparativi tra isterectomia ed uso di LNG-IUS, riportano un peggioramento della sessualità con l’uso del LNG-IUS. Una recente ampia review sui lavori degli ultimi 30 anni che esaminavano la relazione tra contraccettivi orali e libido ha mostrato che non vi sono determinanti biologiche o ormonali che esplichino tale effetto, concludendo che la risposta sessuale sembra rappresentare una complessa combinazione idiosincrasica di effetti sociali, biologici e psicologici. Saranno necessarie ulteriori ricerche per confermare o smentire i dati da noi osservati.Objective: Aim of the study was to evaluate effect on menstrual cycle of a levonorgestrel- releasing device (Mirena®), on quality of life and on sexuality. Methods: During the 36 months of recruitment, 128 women consulting the Family Planning Clinic requesting contraception and satisfying all inclusion criteria were enrolled in the study. Women’s age ranged between 26 and 49 years (mean 38.5 years). At recruitment, obstetric and personal history was taken, as well as a vaginal smear, and general and pelvic examination, including an ultrasound scan were performed; subjects with abnormal Pap-smear or chlamydia infection and women with uterine cavity distortion (e.g. a submucous fibroid) were excluded from the trial. Initial follow-ups were scheduled at 3 and 6 months post-insertion; thereafter women were seen twice a year. Follow-up consisted of a gynaecological examination and a pelvic ultrasound scan. A vaginal smear was repeated every year, or whenever clinically indicated.Each subject was given a menstrual diary to report both menstrual patterns and side effects. Moreover, at screening and after 6 months the Female Sexual Funcion Index (FSFI) and the EQ-5D questionnaires were admeinistered to assess quality of life and sexuality. Results: In our sample 86.7% of women had at least one term pregnancy, while only 13.3% were nulliparae. Over the 4608 woman/months of observation, no pregnancy occurred. Menstrual blood flow decreased in all patients, both in terms of quantity and duration. In the vast majority of cases (91.0 %), spotting disappeared within 6 months; within the fist 6 cycles post-insertion, amenorrhoea occurred in 29.5 % of all women. In five subject the device was removed before the planned 5 years of observation: two women desired a pregnancy and achieved it within six months; three, on the other hand, in spite of a pre-existing condition of menorrhagia, requested removal within the first 9 months, because they could not tolerate amenorrhoea. Three expulsion and one dislocation of the device were, all within the first 8 months. Worth of mention is the fact that, at three months, a pelvic ultrasound scan showed, in 3 women (6%), the presence of ovarian cystic structures (with a diameter up to 5 cm), that resolved spontaneously within 60 days. Data form the EQ-5D questionnaire showed a significative improvement of the quality of life. The results of the FSFI questionnaire showed a significative modification only on sexual desire and pain domain, with interpersonal difference. Conclusion: The LNG-IUS is a safe and effective contraceptive device, particularly indicated in women with heavy or prolonged bleeding. The only important side effect reported was breast tenderness; in addition the transient appearance of ovarian cystic images was observed. A significative effect on quality of life was observed as reported form other studies. The effect on sexuality, showed a significative change on sexual desire and pain, opposite to what reported by a study comparing the LNG- IUS to hysterectomy. It is still to demonstrate if the positive effect on sexuality is due to the better quality of life or to a direct effect of the progestin on the brain

IL RITARDO SCIENTIFICO NELL’INDAGARE LA SESSUALITA’ FEMMINILE

Nella lingua italiana la parola sesso è utilizzata per indicare il genere (gender) maschile o femminile oppure con riferimento all’attività sessuale. Il termine “sessualità” ha invece un significato più ampio perché comprende tutti gli aspetti della vita legati alla realtà del proprio genere (gender). Secondo Masters & Johnson (1), questo termine indica una dimensione della personalità e non soltanto la capacità di un individuo a reagire ad uno stimolo erotico. E’ per questo motivo che la sessualità femminile è così diversa da quella maschile e va studiata separatamente non solo nei suoi aspetti fisiologici, ma – anche e soprat-tutto – nei suoi aspetti psicologici. Sigmund Freud (2) ha affermato che non dovrebbero esservi dubbi su ciò che deve intendersi per “sessuale”: Il sessuale è innanzi tutto lo sconveniente, ciò di cui non è lecito parlare. Questa definizione illustra molto bene una delle ragioni per le quali nel corso della storia umana si è sempre stati riluttanti ad indagare, a studiare le problematiche relative alla sessualità: chi l’avesse fatto avrebbe corso il rischio di essere anche lui considerato sconvenienete, come l’oggetto delle sue indagini. La “saggezza popolare” ha così ritenuto che, trattandosi d’atti privati, tali essi dovessero sempre restare

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. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved

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)

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%)

Selective progesterone receptor modulators 2: Use in reproductive medicine

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. 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. 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. 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