The perinatal origins of major reproductive disorders in the adolescent: Research avenues.

The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies.

Potential role of endometrial stem/progenitor cells in the pathogenesis of early-onset endometriosis.

The pathogenesis of early-onset endometriosis has recently been revisited, sparked by the discovery of endometrial stem/progenitor cells and their possible role in endometriosis, and because maternal pregnancy hormone withdrawal following delivery induces uterine bleeding in the neonate. The neonatal uterus has a large cervix to corpus ratio which is functionally blocked with mucous, supporting the concept of retrograde shedding of neonatal endometrium. Only 5% show overt bleeding. Furthermore, the presence of endometriosis in pre-menarcheal girls and even in severe stage in adolescents supports the theory that early-onset endometriosis may originate from retrograde uterine bleeding soon after birth. Endometrial stem/progenitor cells have been identified in menstrual blood suggesting that they may also be shed during neonatal uterine bleeding. Thus, we hypothesized that stem/progenitor cells present in shedding endometrium may have a role in the pathogenesis of early-onset endometriosis through retrograde neonatal uterine bleeding. During the neonatal and pre-pubertal period, shed endometrial stem/progenitor cells are postulated to survive in the pelvic cavity in the absence of circulating estrogens supported by niche cells also shed during neonatal uterine bleeding. According to this hypothesis, during thelarche, under the influence of rising estrogen levels, endometrial stem/progenitor cells proliferate and establish ectopic endometrial lesions characteristic of endometriosis. This New Research Horizon review builds on recent discussions on the pathogenesis of early-onset endometriosis and raises new avenues for research into this costly condition.

Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion.

Endometriosis in the adolescent has, in recent years, been discovered to be a challenging problem in gynaecology. Although the pain may start at a young age, even before the onset of menstruation, the diagnosis by laparoscopy is almost always postponed for several years, by which time destructive lesions have affected the tubo-ovarian structures and severely compromised fecundability. Several factors may play a role, but one important reason for this disease progression is likely to be the delay in diagnosis. Therefore, transvaginal ultrasounds and transvaginal access with a less invasive needle endoscopy are recommended for exploration of the pelvis, diagnosis of endometriosis and treatment at an early stage before severe lesions develop.

Early stage management of ovarian endometrioma to prevent infertility.

There are now convincing data showing that cystectomy of the endometrioma is not only no cure of infertility, but may harm follicle reserve. The question arises why is cystectomy for an endometrioma, in contrast with other -benign cysts, a risk for follicle reserve and how can ovarian damage be prevented. Surgical specimens of ovaries with endometrioma in situ show in the majority of cases manifestly a combined -extra-ovarian and intra-ovarian pathology with the cortex invaginated to form a pseudocyst. The extra-ovarian pathology includes endometrial lining of the cortex, bleeding and adhesions with surrounding tissues. The intra-ovarian pathology is characterized by microscopic stromal implants, fibrosis, smooth muscle metaplasia and -arteriosclerosis, all affecting follicle reserve in the endometrioma bed. Clinically, ovarioscopy allows differential diagnosis (e.g. luteal cyst) and evaluation of the degree of fibrosis and darkening of the cortical wall. Transvaginal colour Doppler sonography can demonstrate the presence and extent of devascularisation in the endometrioma bed. Given this reality, surgery should be based on evaluation of the pathology of the endometrioma bed, but not on the mere size of the chocolate cyst. The main clinical problem is indeed the delayed diagnosis and consequently advanced irreversible cortical damage. Therefore, the sooner endometriomas are diagnosed, the better, because it increases the chances that vascularisation of the endometrioma bed is preserved. Finally, ablation, but not excision is the treatment of choice. The diagnosis of endometriosis is traditionally based on laparoscopy, but in a sexually active adolescent transvaginal endoscopy can be proposed.

Unmet needs and knowledge of postpartum contraception in Italian women.

PURPOSE OF INVESTIGATION: Clinic visits during pregnancy and puerperium provide a unique opportunity to counsel women on contraception practices. With the aim of evaluating postpartum contraceptive attitudes among urban women attending an antenatal care center and delivering in the same facility, a structured questionnaire was administered to assess desired and received information on contraception in the postpartum period. RESULTS: A total of 436 consecutive interviews were collected during the study period. Pregnancy was unplanned in 39% of the women interviewed. Overall, 269 women (61.7%) had decided to use a method of family planning during postpartum. Among the 112 women who stated they did not want to use a method during postpartum, almost 50% stated that they "did not think they needed it", due to a perceived lack of real risk. Of the 436 women interviewed, only 5.5 % women acknowledged that they had received information on contraceptive use. CONCLUSION: The present study indicates a need for ante- and postpartum counseling of women even in urban areas of Italy.

Defective myometrial spiral artery remodelling as a cause of major obstetrical syndromes in endometriosis and adenomyosis.

Endometriosis and adenomyosis are characterized by the presence of ectopic endometrium, but are also associated with functional and structural changes in the eutopic endometrium and inner myometrium. Alterations in the inner myometrium occurring in women with endometriosis and adenomyosis may be at the root of a defective remodelling of the myometrial spiral arteries from the onset of decidualization and result in vascular resistance and increased risk of defective deep placentation. The association of major obstetrical syndromes and different types of defective remodelling of the myometrial spiral arteries has been well documented. The possibility of a link between both endometriosis and adenomyosis and some major obstetric syndromes remains controversial because of at least two factors: first, changes of the inner myometrium are frequently present in women with endometriosis but the diagnosis requires high-resolution imaging such as magnetic resonance which is not routinely performed and second, patients with endometriosis are frequently subjected to prolonged hormone suppressive therapy. Indeed, there is evidence that pre-treatment with a Gonadotropin Releasing-Hormone analogue can improve the uterine microenvironment and implantation rate following IVF in infertile patients with endometriosis.

Social and ethical determinants of sexuality: gender and health.

The aim of this paper is to expand concepts of gender and explore how behaviours associated with sexual identity affect health risks, as well as the right to sexual expression for sexual minorities and persons with disabilities, to promote safe sexual behaviour and reduce the incidence of sexually transmitted diseases, through the internationally sanctioned Sexual and Reproductive Health concept. During the XX century the multiple meanings of sexuality have been progressively recognized and its physical and psychological health dimension have become a reality, enshrined in United Nations (UN) documents. Countries have begun to adapt their legislations to this new reality and Conventions today guarantee equal sexual and reproductive rights to persons with disabilities, while the nature of variant sexual behaviours is being debated. Sexual and reproductive health is today an acknowledged goal for every individual and the right to equality for persons with variant behaviours and disabilities, as well as the coexistence of diverse meanings of sexuality an established fact. Healthy and safe sexual behaviour should become an important goal for all societies and cultures.

Social and ethical determinants of human sexuality: 1. The need to reproduce.

Aims of this study was to review the many and diverse factors conditioning human sexual behavior; starting with the first and still most important: the need to reproduce and to analyse these factors and how they have changed over time in order to better understand the interplay between the major determinants of human sexuality. For this aim the authors made a literature review of relevant scientific papers and books, including religious websites. At the dawn of humanity, sexuality was focused on reproduction; this, however, did not exclude other important meanings in sexual relationships, since non-conceptive copulations have been a constant aspect of human behavior, becoming an almost unique feature of genus homo. In this respect, the characteristics of a female continuously accessible to her male set the stage for a trend towards monogamy and created the substrate for closed families. Anthropologists have justified conceptive sexuality because sexual activity is costly in terms of energy consumption; for this reason, in the early days, restricting sexual activity made sense for the survival of the species. Traditional ethical considerations and ancient norms by the three major monotheistic religions have favored conceptive sexuality, restricting sexual activity to sanctioned unions and insisting that the major scope of sexuality is procreation. In spite of this, among humans sexuality has always had a wider meaning to the point that for millennia, humans have tried to separate its unitive and procreative meanings. Today much has changed since reproduction can be achieved without intercourse, further separating it from sexual activity. In humans sexuality always possessed multiple meanings, first and foremost reproduction and the creation of a bond between a man and one or several women.

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: state of the art and future perspectives.

Attempts at controlling female fertility through the utilisation of hormonal extracts date back to the beginning of the 20th century, however, practical applications in the human species were only possible when Gregory Pincus had the excellent idea of mimicking the effect of progesterone in blocking ovulation and, through this mechanism, inhibit fertility. It is important to notice that, over its 50 years of history, the original method for hormonal contraception (HC), universally known as ''the pill'', developed into a variety of modalities that today utilise a number of new routes of administration. HCs of today are exclusively made up of either oestrogen-progestin combinations or progestins alone. This does not mean that no attempt has been made to use other classes of steroids for contraception. The best known compounds tested are the so-called ''antiprogestins'', more precisely called selective progesterone receptor modulators (SPRM). Hormonal contraceptives, originally administered in the form of daily pills, can be utilised today through seven different routes: intramuscularly, intranasally, intrauterus, intravaginally, orally, subcutaneously, and transdermally. New strategies in the field of oral contraception include further dose reduction, the synthesis of new active molecules and new administration schedules. Newly marketed 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 is now well established, as 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 oestrogen and a progestin. A new minipill (progestin-only preparation) containing desogestrel has been recently marketed in a number of countries and is capable of inhibiting ovulation in most women. After the first device capable of delivering progesterone directly into the uterus was withdrawn, a new system releasing locally 20 microg over 5 years, is today widely marketed with excellent contraceptive and therapeutic performance. Finally, several subcutaneously implanted systems have been also developed in the form of contraceptive ''rods'', where the polymeric matrix is mixed with the steroid and ''capsules'', made of a hollow polymer tube filled with free steroid crystals. 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 SPRM.

[Infertility: a global perspective]. / Infertilitá: una visione globale.

Infertility has always existed; however, today it has a different meaning because the possibility exists, not only to treat it in some three quarters of all cases, but also, in a number of instances, to prevent it. At the same time, this improved scenario created a number of important new issues concerning public health policies and the social impact of infertility; these issues can be summarized with two words: equity and ethics. Indeed, there are intolerable differences in access to infertility care, depending on the social-economic status, as well as the country in which a couple lives. It is generally believed that, overall, in the general population a persistent form of infertility affects some 7-8% of all couples; in Europe the prevalence of infertility has been estimated at around 14%. There are important regional differences in the incidence and causes of sterility. Whereas the best known factor in western countries is an increase in the age in which women attempt to conceive, in Africa, the most important cause is represented by sexually transmitted infections. Over the last fifty years there have been major break-throws in the diagnosis and treatment of infertility, although it must be stressed that the importance and validity of therapy must be in all cases evaluated against expectant management. This is because in couples without clear signs of functional or organic pathology, conception will occur spontaneously in between 80 and 90% of the cases. At the same time, if attempts to conceive fail over a period of three years, even in women 30 years or younger, the probability of pregnancy decreases to about 40%. Finally, it must be stressed that advances in assisted reproductive technology have created not only important successes, but also significant ethical problems: on the one hand, the debate is open on the limits of artificial interventions in the field of reproduction; on the other the possibility exists that a partner may ''impose'' an infertility on the other.

Reasons for requesting emergency contraception: a survey of 506 Italian women.

OBJECTIVE: To evaluate the reason for requesting emergency contraception (EC), previous use of contraceptive methods and provision route in a Family Planning Clinic in Italy. METHODS: Women requesting EC were interviewed, through a questionnaire containing questions on demographic characteristics, about their reasons for requesting EC, their prior contraceptive use, their reasons for not using an effective contraceptive method (or possible reasons for its failure) and specifically about the so-called 'provision route' (i.e. whether and where they had previously requested EC receiving a negative response). RESULTS: Almost 70% of all women requesting EC were aged between 18 and 25 years. Some 80% of all women were in a stable relationship with their partner, with fewer than 20% having had an occasional intercourse. The vast majority of women (83%) reported prior use of a modern contraceptive method, i.e. 64% with a condom, 27% for combined oral contraceptives and 1.1% for the intrauterine device (IUD). In addition, 15% of the women had used more than one method (oral pills and condoms). Concerning the reasons for requesting EC, condom breakage or slipping was the most frequently cited (64%), followed by totally unprotected intercourse (28%), failed withdrawal (5%) and forgetting one or more pill (only 1.1%). CONCLUSIONS: More than one-third of the women interviewed had previously used an emergency contraceptive modality; although no one did so more than four times. Therefore, it can be inferred that-at least in the present series-EC had not been used as a routine contraceptive method. Finally, it seems clear that in Italy, even in large cities, information about the availability, proper usage and mechanism of action is lacking. This seems due to information being spread by word of mouth between peers and friends, with more formal communication channels lagging behind.

[The meaning of fertility control in an integrated world]. / Significato del controllo della fertilità in un mondo integrato.

Modern contraception was born out of the momentum of the demographic explosion that characterised the 20th century; today the phenomenon has acquired complexity because it is interconnected with population aging which is already very evident in the industrialised West, but is about to explode in the developing world too. Modern contraception played a decisive role in slowing down demographic growth which is now at a point below replacement level in numerous industrialised countries, including Italy. A phenomenon that has, unfortunately, often accompanied family planning education campaigns has been that of coercion: in the most highly populated countries and thus in those countries most exposed to the severe consequences of ultra-rapid increases in the population, governments and particularly zealous public servants have often resorted to more or less forced sterilisation and even abortion in order to achieve their targets. All of this ended in 1994 when the Cairo International Conference for Cooperation and Development recognised and sanctioned the new integrated concept of Reproductive Health. This new concept mandates that family planning and modern contraception must be integrated with all other interventions aimed at creating a state of psychophysical wellbeing in everything that concerns reproduction. Today then it is absolutely impossible to speak of "family planning", "fertility control" or "contraception" in isolated fashion; it is necessary to insert interventions in these fields into the global context of all other interventions in matters of reproduction. Finally, it should be recalled that in the 2nd half of the 20th century, after hundreds of thousands of years, homo sapiens performed at least 2 revolutions: the contraceptive revolution, which permitted sexuality without reproduction, and the reproductive revolution, which permitted reproduction without sexuality. Given the speed of these changes it should not surprise that they were received with suspicion, not to say fear or panic. Progress should, however, be welcomed favourably provided it does not change the essence of the relationship between parents and children and the biological balance that sustains them.

Why a consensus conference on hormone replacement therapy and the cardiovascular system?

A recent randomized, placebo-control study of a combination of conjugated estrogens (0.625 mg) and medroxyprogesterone acetate (2.5 mg) known to bring considerable advantages to post-menopausal women, has concluded that the risks associated with its use outweigh the benefits. On the strength of these data the manufacturer began recommending that physicians consider alternatives to their product to treat post-menopausal symptoms. Since women take hormone replacement therapy (HRT) for compelling health reasons, it is important, not only to evaluate the new evidence, but also to translate it into terms which can be understood by women and their physicians. Although the focus of this conference is on the cardiovascular system, in order to place the present controversy in its proper perspective, it is necessary to consider also other adverse effects that frighten women, first and foremost, a possible increased risk of breast cancer. For several years it has been reported that there is an increased risk of invasive breast cancer with increased duration of HRT use, similar to what has been found for oral contraceptives. The situation is however, entirely different when addressing HRT and risk of cardiovascular diseases (CVD). Here, a large body of evidence has, for years, pointed to a protective effect. Therefore, in the case of cardiovascular risk, we must proceed very cautiously and weigh the evidence, before concluding that HRT has indeed a negative effect on cardiovascular diseases. To properly do so, we must evaluate the validity and applicability of the findings presented in the latest study, since evidence indicates that the results of the study may not be applicable to women seeking HRT at the time of menopause. We also need to try and outline an overall "risk-benefit profile" for the use of HRT and we must aim at establishing a true dialogue between all parties concerned. Finally, we must obtain information, or state the lack of it, on possible different effects among the various estrogens, routes of administration and dosages, as well as possible different actions of the various progestins, their dosages and routes of administration.

Clinical profile of contraceptive progestins.

The term progestogen has been widely utilized to indicate the general class of agents that includes both progesterone and its synthetic analogs, whereas the term progestin refers only to synthetic progestational steroids. The development of progestins has been influenced in a major way by the search for orally active hormonal contraceptives, since it is likely that hormonal contraceptives will continue to utilize a progestin, the only possible alternative being represented by the utilization of antiprogestins. Synthetic progestogens in clinical use today belong to three main chemical families: progesterone derivatives (progesterone, retro-progesterone, 19-norprogesterone and 17alpha-hydroxyprogesterone); gonane and 19-nortestosterone derivatives (norethisterone, levonorgestrel, desogestrel, gestodene, norgestimate); a spironolactone derivative. Biological potency of progestogens varies depending on the end-point measured, usually ovulation inhibition and endometrial transformation; with both these tests, the most active compounds are all gonane derivatives, with a potency over a 100 times that of the natural hormone. When administered in adequate doses, a progestin inhibits fertility by inhibiting ovulation. This action is mainly exerted at the hypothalamic level where, physiologically, progesterone decreases the number of LH pulses. When progestogens are delivered directly to the uterine cavity, their action seems to be purely local. It has been amply proven that--even when administered in doses that do not constantly inhibit ovulation--a progestin can still remain effective as a contraceptive by acting at the level of the cervical mucus and, at least in part, of the endometrium. Progestogens utilized today differ largely in their pharmacokinetics. In general, after intake, these compounds are rapidly absorbed and distributed so that peak serum concentrations are reached between 1 and 4 h. Third-generation progestins (desogestrel, gestodene, norgestimate) have common characteristics: a higher affinity for progesterone receptors than their predecessors, a lower affinity for androgen receptors, a higher selectivity of action, a higher central inhibitory activity, a higher potency at the level of the endometrium, and an overall metabolic neutrality, in terms of effects on lipid and carbohydrate metabolism. In general, progestins can induce two types of adverse effects: changes in lipid metabolism and bleeding irregularities. Whereas the newer compounds seem to have overcome the first of these adverse effects, the second remains untouched: to this day, proper cycle control can only be achieved with combined hormonal contraceptives.

Safe motherhood: the FIGO initiative.

Over the last twenty years the international community-realizing that the tragedy of women dying during pregnancy and in childbirth could no longer be tolerated-launched a series of initiatives aimed at making safe motherhood a cornerstone of health services in all countries. Making pregnancy and delivery safe events is particularly complex, as it involves infrastructural and logistic, as well as technical, issues. Women die because they have no access to skilled personnel during pregnancy and at the time of delivery and because--if an emergency situation arises--they cannot reach a facility where emergency obstetric services are available. FIGO, the International Federation of Obstetrics and Gynecology-as the only global organization representing the Obstetricians of the world-decided some time ago that it could not limit its activities to proposing technical guidelines and debating scientific issues. It had to move into the field and, through its affiliated societies, help change the ability of the multitude of women in the developing world to obtain skilled attendance at birth. In 1997, plans were made to launch activities in five areas where maternal mortality was particularly high: Central America (Guatemala, Honduras, Nicaragua and El Salvador), Ethiopia, Mozambique, Pakistan, and Uganda. Five member societies from the developed world (the American College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynecologists of Canada, the Italian Society of Obstetrics and Gynecology, the Royal College of Obstetricians and Gynecologists of the United Kingdom; and the Swedish Society of Obstetrics and Gynecology) agreed to provide support to their counterparts in these five selected areas. The project is now in its final stage. Results are, by and large, positive, demonstrating that, by motivating health professionals in the field and for a relatively modest financial outlay, more efficient use of existing services could be made in a sustainable fashion to save lives.