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.

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.

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.

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.

Effect of pH on the structure and aggregation of human glycodelin A. A comparison with beta-lactoglobulin A.

The effect of pH on the structure of glycodelin A (GdA) and of beta-lactoglobulin A (beta-LgA) has been investigated by means of circular dichroism, steady state fluorescence, synchrotron radiation small angle X-ray scattering (SR-SAXS) and gel permeation chromatography. The comparison between GdA and beta-LgA shows that, at pH 7.0, both proteins are dimers with an extended content of beta-sheet conformation, but pH 2.0 and 9.0 yield a different secondary, tertiary and quaternary structural organisation. Whilst beta-LgA is a monomer, that conserves beta-sheet conformation at pH 2.0 and 9.0, GdA has a stable dimeric structure at alkaline pH, but at pH 2.0 increases its alpha-helix content and it aggregates soon. SR beam has been used to perform SAXS comparative measurements of the two proteins. SR-SAXS data provide the radius of gyration and the radii of the cross-section and of the thickness. GdA aggregation at acid pH has been characterised by calculating the distance distribution function (P(r)). Isoelectric focusing and chromatofocusing data show a different charge distribution on the surfaces of the two proteins, supporting the hypothesis that the presence of oligosaccharides deeply influences the conformational state and the aggregation process of GdA at different pH values. In particular, the presence of sialic acid residues, within the oligosaccharide moiety of the GdA, might be responsible for the differences observed between the two proteins.

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.

Long acting contraceptives. Present status.

Long acting injectable hormonal contraceptives are among the most effective fertility regulating agents developed; yet they are also among the most controversial because of animal data indicating a possible carcinogenic potential in several species. A critical analysis of these animal findings has revealed, in all instances, the existence of specific mechanisms not occurring in the human. For this reason, most national and international scientific bodies who have reviewed this issue have concluded that there are no toxicological reasons for not using long acting hormonal contraceptives. Long acting agents can be divided into 2 separate groups: those having a duration of action of one month, which are composed of a long acting oestrogen and a progestagen, and those lasting for several months which consist of only a progestagen. Among the injectable progestagen-only contraceptives tested, only 2 have so far reached the international market: depot medroxyprogesterone acetate (DMPA), which has been administered at 3- or 6-month intervals and norethisterone enanthate, which has been injected at intervals ranging between 2 and 3 months. The most important side effect observed with these 2 agents is a complete disruption of the menstrual bleeding pattern, leading - in some cases - to total amenorrhoea, which is more frequent with depot medroxyprogesterone acetate than with norethisterone enanthate. The latter, however, has a shorter duration of action with a higher pregnancy rate than the former. Other adverse reactions are rare and of no real importance. Metabolic effects with progestagen-only injectable preparations are, in general, mild and less marked than with combined oestrogen-progestagen formulations. Recent investigations have shown that the return of fertility following their use is delayed but in no way impaired. Monthly injectable oestrogen-progestagen combinations have been tested to a more limited extent and these agents are available only in a very few countries. Their main advantage over progestagen-only preparations is that they allow a reasonable menstrual bleeding pattern in the majority of cases. Their obvious disadvantage is that they contain a long acting oestrogen.

Zoladex (goserelin acetate) and the anemic patient: results of a multicenter fibroid study.

OBJECTIVE: To compare the effects of goserelin acetate treatment with or without iron with iron alone. DESIGN: Multinational, multicenter, prospective, randomized, double-blind study. PATIENTS: Premenopausal women with menorrhagia or metrorrhagia and anemia associated with uterine leiomyomata awaiting hysterectomy. INTERVENTION: Patients were randomized to one of three 12-week treatment groups namely goserelin acetate 3.6 mg once monthly plus placebo iron; 3.6 mg goserelin acetate once monthly plus 600 mg/d iron; or sham injection once monthly plus 600 mg/d iron. MAIN OUTCOME MEASURE: Preoperative hemoglobin concentration; preoperative uterine and fibroid volumes and operative blood loss. RESULTS: Considering the entry and preoperative hemoglobin concentrations, there was a difference in least square means of just over 1 g/dL between the goserelin acetate plus iron and iron only groups and 2.6 g/dL between the goserelin acetate plus iron and goserelin acetate only group. These differences were both statistically significant. Uterine and fibroid volumes were decreased in the goserelin acetate-treated patients by between 37% and 40% and 44% and 47%, respectively, compared with 7% decreases for both in the iron only group. The differences in absolute changes were statistically significant for both the goserelin acetate-treated groups versus the iron-treated group. The least square geometric mean operative blood loss was greatest in the iron only group. CONCLUSION: In the patient with uterine leiomyomata and anemia, goserelin acetate in combination with iron therapy has shown significant advantages over the iron alone in restoring hematologic normality, decreasing uterine and fibroid volumes, and reducing operative blood loss.

Return of ovarian function and endometrial morphology in women treated with norethisterone oenanthate: a pilot study.

A comparative pilot study was undertaken in three centers to determine the time of return of ovulation after the injection of the steroidal contraceptive norethisterone oenanthate (NET-OEN). The effect of the compound on the endometrium and some properties of cervical mucus were also assessed. Increases in plasma progesterone levels suggested that ovulation resumed in all six women in Bahia within 60 days of injection of NET-OEN, whereas in Bangkok and New Delhi only two women in each center ovulated within this time. The difference in the time of return of ovulation between women in Bahia (mean time 42 days) and those in Bangkok and New Delhi (92.5 days) was statistically significant. Follicular function returned earlier than luteal function: all six women in Bahia and Bangkok and five of the six in New Delhi showed evidence of follicular activity within 60 days. All endometrial biopsies, obtained at a time of increased progesterone production, were secretory and suggested that administration of the gestagen did not exert a prolonged suppression of endometrial activity. In general, changes in cervical mucus were consistent with variations in plasma steroid levels.

Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme.

The great demand for improved long-acting injectable steroid contraceptives, particularly in developing countries, and the relative lack of interest from the pharmaceutical industry to develop such products stimulated WHO to launch a synthetic and screening programme to find improved, safe and acceptable injectable preparations. More than 210 esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) have been prepared in university-based research laboratories situated mainly in developing countries, and then screened by NICHHD in animal models. The following three compounds, levonorgestrel butanoate, cyclopropylcarboxylate and cyclobutylcarboxylate, proved to be particularly long-acting when administered as microcrystalline suspensions. The overall strategy of this research and development programme is described.

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.

Non-surgical female sterilization with quinacrine: an update.

The intrauterine installation of quinacrine represents a simple, inexpensive, effective, and seemingly safe method of non-surgical female sterilization. Existing clinical data on its use are very encouraging: Results of a large study conducted in Vietnam with an overall sample of over 30,000 women showed high effectiveness; in addition, when a retrospective study was conducted in these women, cumulative 5-year pregnancy rates were estimated to be 13% in women younger than 35 years and 6.8% in the women older than 35. Overall, failure rates with quinacrine have been estimated, at 10 years, to be between 1.9 and 4 times higher than those obtainable with conventional surgical procedures of tubal interruption. Unfortunately, existing toxicology for topical use of quinacrine pellets is incomplete. This prompted an expert group convened by WHO, to comment, in 1994, that the toxicology of locally applied quinacrine is inadequate. To counter this statement the proponents of the method argue that it is unfair to apply the stringent pre-clinical requirements that are mandatory in the industrialized world, to methods utilized in countries plagued by both high fertility and high maternal mortality. This controversy will soon be resolved since conventional toxicological evaluation is now underway. In conclusion, the future of quinacrine for non-surgical female sterilization will depend on the results of long-term animal studies, as well as the retrospective human studies now being carried out.

The Depo-Provera debate. Commentary on the article "Depo-Provera, a critical analysis".

A widely publicized article has in recent months caused a great deal of concern among individuals interested in responsible promotion of family planning. The article contains a long series of factual errors, distortions and biased quotations. This commentary presents evidence, based on current knowledge, that Depo-Provera is a satisfactory contraceptive with several advantages and some disadvantages, and poses no more unresolved problems than oral contraceptives. There is no evidence that, at contraceptive doses, it increases the risk of cancer, impairs bone mineralization, "shocks" the hypothalamus, damages the liver or the immune system, or causes premature aging. Studies to date have not shown damaging effects on infants exposed to the drug in utero or via breast milk. To most women, disruption of the menstrual cycle, the major side effect, is not a health hazard. Finally, women in various parts of the world have shown to be quite capable of choosing for themselves whether or not the advantages of the drug can overcome the disadvantage of almost certain menstrual disturbance.

Comparative clinical evaluation of the effect on carbohydrate and lipid metabolism of two norethisterone-containing hormonal contraceptives: Mesigyna and TriNovum.

The effect on carbohydrate and lipid metabolism of two hormonal contraceptive preparations containing norethisterone (commercially known as Mesigyna and TriNovum) was studied in a total of 60 women, before and after 6 months of treatment. Carbohydrate metabolism was evaluated by means of a euglycemic glucose clamp test; lipid metabolism was monitored by measuring total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, and triglycerides. The two groups were properly matched with the exception of pretreatment levels of cholesterol and LDL-cholesterol. At the end of treatment, no difference was found within or between groups in fasting glucose and insulin levels and in glucose rate of disappearance. A significant increase in total cholesterol, HDL-cholesterol, and VLDL-cholesterol was found in both groups at the end of the treatment period; in addition, TriNovum caused a significant increase also in triglycerides. In conclusion, the safety of both preparations with regard to carbohydrate metabolism was confirmed using the most accurate method available; furthermore, changes in lipid metabolism were such as to have little clinical significance.

A preliminary pharmacological trial of the monthly injectable contraceptive cycloprovera.

A comparative pharmacological pilot study of the monthly injectable contraceptive CycloProvera was carried out in 11 women in four centres. There were no significant differences in the results between the centres except that the injection-bleeding interval appeared to be shorter in Swedish women than in those in Havana and Mexico. Medroxyprogesterone acetate was detectable in blood for 28 to 62 days after injection of CycloProvera and although follicular activity returned in less than 28 days after injection in many of the women, corpus luteum function was suppressed for at least seven weeks in all women. Most of the women retained a regular menstrual pattern; six of 33 cycles were amenorrhoeic. There was no significant change in any of the biochemical and haematological analyses.