Giuseppe Benagiano

Structural and molecular features of the endomyometrium in endometriosis and adenomyosis

BACKGROUND Adenomyosis and endometriosis were initially described as adenomyoma. When the retrograde menstruation theory became widely accepted to explain the pathogenesis of endometriosis, since it does not explain adenomyosis, the two conditions came to be seen as distinct entities. However, emerging evidence suggests that both diseases may be linked to changes in the inner portion of the myometrium. In addition, similar anomalies were found in the eutopic endometrium of the two conditions and the debate has re-opened. A common origin for both adenomyosis and endometriosis would have relevance not only for understanding uterine function and pathophysiology, but also for clinical management and treatment. METHODS The Scopus and Medline databases were searched for all original articles published in English up to the end of 2012. Search terms included adenomyosis; endometriosis; endometrium; eutopic endometrium; inner myometrium; junctional zone. Special attention was paid to articles comparing features of eutopic endometrium in the two conditions. RESULTS A number of similarities exist between adenomyosis and endometriosis and, by using magnetic resonance and laparoscopy, it was found that, at least in some subgroups, the two conditions often coexist. In both situations the inner myometrium (or junctional zone) is altered, although alterations are much more marked in adenomyosis where a thickness >12 mm is today considered sufficient for diagnosis. Research has shown differences between the eutopic endometrium of women with both diseases when compared with controls. There is an immune dysfunction and there are alterations of adhesion molecules, cell proliferation and apoptosis. An increase in cytokines and inflammatory mediators has also been observed. Finally, the presence of oxidative stress and anomalies in free-radical metabolism may alter uterine receptivity. When the two conditions were compared, dissimilarities were also observed in the extent of apoptosis inhibition and in the expression of some inflammatory mediators. It is not clear if observed differences are primarily related to presenting symptoms. Finally, both conditions are steroid dependent and research suggests a role for epigenetic mechanisms. The analysis indicates that much of the published research may have been influenced by the method of diagnosis and/or has not been controlled for the presenting symptoms, the concomitant presence of both diseases or full consideration of fluctuations within cycle phase. CONCLUSIONS It is difficult to draw firm conclusions from existing evidence since major diagnostic limitations still exist and there is a systematic bias in clinical presentation. In addition, scanty information is available on the natural history of endometriosis and no studies exist on the natural history of adenomyosis. Notwithstanding these limitations, a number of similarities, but also some differences have been found between the eutopic endometrium in the two diseases. These findings need to be taken with considerable caution as the few instances where the research was repeated yielded conflicting results.

Biodegradable systems for the sustained release of fertility-regulating agents.

n Biodegradable or erodible delivery systems are represented by contraceptive devices where the matrix also dissolves and both the drug and the systems components reach systemic circulation. One promising feature of such a system is the possibility of achieving programmed release whereby the active component is made available only during specified periods. A major drawback of the system is that if the device were made of microparticles, the occurence of a serious adverse reaction can be counteracted only by administration of other active principles, and not by simply removing the implant. Another drawback is that the components diffuse into systemic circulation, requiring careful long-term toxicological evaluation of hyrolysis products of the biopolymer making up the matrix. Various mechanisms are involved in the release of the active drug: these include erosion; diffusion; a combination of both, and the cleavage of a covalent linkage between the drug and the polymer backbone. Systems currently being developed include devices made of of: 1) polylactin and/or poly-glycolic acid; 2) polymers derived from e-caprolactone; 3) polypeptide polymers; 4) ploy-glutamic acid to which steroids are covalently bound, and 5) polyorthoester known as Chronomer.n

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.

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.

Risk of obstetrical complications in organ transplant recipient pregnancies.

Pregnancy after kidney and liver transplantation is becoming relatively common, although, in both groups, maternal complications are higher than in the general population. Both mean gestational age and mean birthweight seems significantly greater for liver transplant versus kidney transplant recipients and the risk of hypertension during pregnancy seems also lower for liver transplant than kidney transplant recipients. Thus, sequelae of chronic kidney diseases have stronger adverse effects on pregnancy, leading to a higher occurrence of adverse neonatal complications. Also, gestation in heart recipients may be complicated and preeclampsia seems to occur more frequently. However, the transplanted heart seems to adapt well to changes caused by pregnancy, such as increased cardiac workload and output, and elevated maternal oxygen consumption. More problematic is pregnancy in lung transplant recipients. Spontaneous pregnancy and healthy childbirth after bone marrow grafting is relatively rare due to irradiation, but, if gestation occurs, no specific problems have been identified. Obstetrical syndromes associated with transplantation reflect the pathology of defective deep placentation, where conversion of uterine spiral arteries remains largely restricted to the decidual segment. The myometrial segments of the uteroplacental arteries have a unique vascular memory and are at great risk to develop obstructive, atherosclerotic lesions. A similar increased risk of complications already existed in pregnancies during the years before transplantation. The effect of immunosuppressive therapy remains speculative. Therefore, the main target for improving the outcome of pregnancy in women at risk is the strict antihypertensive treatment from the earliest stage of pregnancy.

The history of endometriosis.

A dispute has recently emerged whether early descriptions exist of the condition we name endometriosis. A first question is: ‘Who identified endometriosis? To respond, two non-complementary methods have been employed: searching for ancient descriptions of symptoms associated with endometriosis or, alternatively, identifying researchers who described pathological features we associate with the presence of endometriosis in its various forms. We opted for the latter and found no evidence that in older times anyone delineated the macroscopic features of endometriosis; descriptions of menstrual or cyclic pain cannot be taken as proof of knowledge of what caused it. During the mid-part of the 19th century, Rokitansky had a great intuition: endometrial glands and stroma can be present in ovarian and uterine neoplasias. However, using histological parameters of endometrial structure and activity, the first scientist to delineate peritoneal endometriosis under the name ‘adenomyoma was Cullen. On the other hand, Rokitansky was the first to describe a form of adenomyosis (an adenomatous polyp). Early descriptions of ovarian endometrioma as ‘haematomas of the ovary or ‘chocolate cysts date back to the end of the 19th century. The first mention of an ‘ovary containing uterine mucosa was published in 1899 by Russel, but Sampson was the first to demonstrate specific endometrial activities, such as desquamation at the time of menstruation and decidualization in pregnancy; subsequently, he presented a theory on its pathogenesis.

Adenomyosis: a life-cycle approach

The life-cycle approach to endometriosis highlighted unexpected features of the condition; the same approach was therefore applied to gain insight into the clinical features of adenomyosis and to draw a comparison with endometriosis. This is possible today thanks to new imaging techniques enabling non-invasive diagnosis of adenomyosis. The specificity and sensitivity of magnetic resonance imaging and transvaginal ultrasound remain uncertain. Unlike endometriosis, little information is available on the presence of classic adenomyosis in adolescents, except for rare cystic forms that may not represent the true disease. Adenomyosis is most likely to affect adult women, although most reported incidences are still based on post-hysterectomy studies, and are affected by diligence in histopathologic diagnosis and the adopted cut-off point. The traditionally accepted associations of adult adenomyosis, such as multiparity, a link to infertility and its effect on pregnancy are uncertain. Active adenomyosis has been found in pre- and peri-menopausal women and in postmenopausal women receiving tamoxifen. In conclusion, major diagnostic limitations and the systematic bias of hysterectomy make it difficult to draw firm conclusions from existing evidence. In addition, no information is available on the natural history of adenomyosis and no study has systematically evaluated its existence in adolescents.

The Special Programme of Research in Human Reproduction: Forty Years of Activities to Achieve Reproductive Health for All

The Special Programme of Research in Human Reproduction (HRP), co-sponsored by the UNDP, UNFPA, WHO, and the World Bank, is celebrating 40 years of activities with an expansion of its mandate and new co-sponsors. When it began, in 1972, the main focus was on evaluating the acceptability, effectiveness, and safety of existing fertility-regulating methods, as well as developing new, improved modalities for family planning. In 1994, HRP not only made major contributions to the Plan of Action of the International Conference on Population and Development (ICPD); it also broadened its scope of work to include other aspects of health dealing with sexuality and reproduction, adding a specific perspective on gender issues and human rights. In 2002, HRP’s mandate was once again broadened to include sexually transmitted infections and HIV/AIDS and in 2003 it was further expanded to research activities on preventing violence against women and its many dire health consequences. Today, the work of the Programme includes research on: the sexual and reproductive health of adolescents, women, and men; maternal and perinatal health; reproductive tract and sexually transmitted infections (including HIV/AIDS); family planning; infertility; unsafe abortion; sexual health; screening for cancer of the cervix in developing countries, and gender and reproductive rights. Additional activities by the Programme have included: fostering international cooperation in the field of human reproduction; the elaboration of WHO’s first Global Reproductive Health Strategy; work leading to the inclusion of ICPD’s goal ‘reproductive health for all by 2015’ into the Millennium Development Goal framework; the promotion of critical interagency statements on the public health, legal, and human rights implications of female genital mutilation and gender-biased sex selection. Finally, HRP has been involved in the creation of guidelines and tools, such as the ‘Medical eligibility criteria for contraceptive use’, the ‘Global handbook for family planning providers’, the ‘Definition of core competencies in primary health care’, and designing tools for operationalizing a human rights approach to sexual and reproductive health programmes.

Quinacrine sterilization: a middle road

Discussion of female sterilization using the trans-cervical application of quinacrine hydrochloride (quinacrine sterilization; QS) has become highly polarized [1,2]. We feel the unreasoned passion about QS is making evidence-based decisions difficult to reach. We have both had executive responsibility for clinical trials on new drugs and devices, with particular reference to developing countries. In the case of QS, we have in the past taken somewhat different policy stands, although always sincerely respecting each other’s points of view. Although we are no longer directly engaged in research in this area, we both wish to help broaden the range of fertility control options available, especially for low income women around the world. We think it would be useful to summarize where we agree, and to invite others also to look for common ground in this area. We both recognize that introducing a new drug or device is a difficult, complex process that demands careful, sincere judgments. Experts do not always like to recognize that they are fallible, and the public does not like to accept an element of uncertainty. However, the introduction of any new drug must necessarily take place on the basis of balanced judgment and, almost inevitably, incomplete information. It always takes a decade or two to gather empiric evidence of safety, based on large-scale actual use. During this interval there are endless opportunities for nonobjective forces to

Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth

Background: Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare, life-threatening event, particularly relevant to women with endometriosis or deciduosis. Methods: To determine the type of lesions leading to SHiP, a literature search was conducted among all published SHiP cases. From a total of 1,339 publications, information on pathological findings at the bleeding site with histological data was found in 24 case reports (16 pregnant, 8 postpartum). Results: Among pregnant women (81% primigravida), 75% had a diagnosis of endometriosis and 25% of deciduosis. Among postpartum women (38% primiparous), 63% had a diagnosis of deciduosis and 25% of endometriosis. In all cases except one, decidual cells, with or without glandular structures, were present at the bleeding site. Decidual vessels were described in 7 cases and all exhibited vascular changes, including distension of the lumen, medial disorganization, or loss of vascular integrity. These vessels were significantly different from arteries seen in the secretory endometrium, showing that structural modifications take place during the initial stage of the remodelling of placental bed spiral arteries. Conclusions: During pregnancy, a link seems to exist between ectopic decidualization, particularly that occurring in endometriotic foci, and occurrence of SHiP. In addition, subclinical decidual bleeding may be a potential risk factor for preterm labour.