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Gonadotrophin-releasing hormone (GnRH) antagonists have been demonstrated to reduce endometriosis-associated pain. Because of the hypo-oestrogenic state they induce, however, higher dosages of GnRH antagonists are not recommended for used long term. This unwanted effect may be eliminated by so-called add-back therapy (ABT). This review was conducted to assess the safety and efficacy of GnRH antagonists, with or without add-back hormonal replacement therapy. Out of the 345 studies selected through the initial search, seven randomized controlled trials were included, comparing different oral GnRH antagonists at varying dosages, from a minimum of 50 mg to a maximum of 200 mg once or twice daily. Women treated with the lowest dose of GnRH antagonists had significantly greater mean pain score reductions from baseline throughout treatment compared with those treated with placebo (odds ratio [OR] -13.12, 95% CI -17.35 to -8.89 and OR -3.08, 95% CI -4.39 to -1.76 for dysmenorrhoea and non-menstrual pelvic pain, respectively). Compatible with the dose-response effect, a positive correlation was found between response rates and adverse event rates. While GnRH antagonists offer an advantage in terms of pain reduction for endometriosis, the more recent literature suggests using GnRH antagonists with ABT, which, while mitigating the hypo-oestrogenic effects of GnRH antagonists, maintain their efficacy, while allowing their long-term use., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The availability of non-invasive diagnostic tests is an important factor in the renewed interest in adenomyosis, as the disease can now be more accurately mapped in the uterus without a need for hysterectomy. An agreed system for classifying and reporting the condition will enhance our understanding of the disease and is envisaged to enable comparison of research studies and treatment outcomes. In this review, we assess previous and more recent attempts at producing a taxonomy, especially in view of the latest proposal for subdivision of adenomyosis into an internal and an external variant. In this context, we also explore the uncertainties linked to classifying involvement of the uterovesical pouch, the pouch of Douglas and lesions in the outer myometrium. Two opposing hypotheses are forwarded to explain the pathogenesis of these variants, namely that disease localized in these areas originates from an invasion by uterine adenomyosis of peritoneal organs; alternatively, that lesions present in the outer myometrium originate from peritoneal endometriosis. At the root of debates around these opposing theories of pathogenesis is fragmentary evidence. Because of the limitations of currently available evidence, and until this issue is resolved, broad agreement on a hypothesis to underpin any proposed classification is unlikely., (Copyright © 2020 Reproductive Healthcare Ltd. All rights reserved.)

Management of ovarian endometrioma is a matter of debate between those advocating early treatment and those believing that cysts less than 3 cm in diameter should not be submitted to surgery. To explore a new approach to its management capable of preserving future fertility, the molecular pathology of ovarian endometrioma is reviewed and mechanisms by which the endometrioma progressively affects the ovary during reproductive life are summarized. The scope of new therapeutic modalities includes restoring the progesterone receptor ratio using progestin or progesterone receptor modulators and decreasing local oestrogen production through an aromatase inhibitor. In addition, free radical production can be blocked by antioxidants and the autophagic process by increasing apoptosis. Finally, metalloproteinases and relaxin activity, as well as the inflammatory process can be controlled. Many of these pharmacological treatments lend themselves to local administration and can be applied through intracystic drug administration; in fact, the intracystic route has already been tried with recombinant interleukin-2, methotrexate and ethanol; the latter to obtain sclerotization. Specifically, it is proposed that endometrial growth in the endometrioma is suppressed by intra-cystic application of synthetic progestins, such as levonorgestrel or danazol, selective progesterone receptor modulators, such as mifepristone, ulipristal or asoprisnil, without affecting ovarian activity., (Copyright © 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

In 2004, The Italian Constitutional Court prohibited treatments involving gamate donation, embryo donation, embryo cryopreservation (except under exceptional circumstances), and the transfer of more than three embryos. Basically three statements were made by the Court: the ban violates a couple's fundamental right to health, to self-determination and to have a child. Here, the consequences of such a decision and the legal challenges that ensued are discussed., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Present management of the ovarian endometrioma focuses on the size of the cyst and dictates that surgery should not be performed unless this exceeds 3 cm, which neglects the complex pathology of this condition. Studies of ovaries with the endometrioma in situ show progressive smooth muscle cell metaplasia and fibrosis of the cortical layer as the main ovarian lesion. There is no correlation between the size of the endometrial cyst and the degree of ovarian pathology: it is the mere presence of an ovarian endometrioma that has a detrimental impact on the cortical layer's follicle reserve. Cystectomy in young patients with an endometrioma may be particularly detrimental to follicle reserve, with the ovarian parenchyma loss at the time of surgery being related to the cyst's diameter. An underutilized diagnostic procedure, transvaginal hydrolaparoscopy with in-situ inspection of the cyst wall by ovarioscopy, allows careful diagnosis of ovarian pathology and selection of appropriate surgery with minimal invasiveness. Thus, available evidence shows that expectant management may not be the best choice when an endometrioma is suspected. On the contrary, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve normal ovarian function. Present management of ovarian endometriomata is based on the size of the cyst and dictates that surgery should not be performed unless this exceeds 3cm. We argue that this approach neglects the true pathology of the ovary, since pioneers have studied ovaries with the endometrioma in situ and demonstrated that progressive smooth muscle cell metaplasia and fibrosis in the cortical layer constitute the main features of an endometrioma. There is no correlation between the size of the endometrial cyst and the degree of ovarian pathology: it is in the first place the mere presence of an ovarian endometrioma that has a detrimental impact on follicle reserve. It has been shown that cyst ablation in young patients with an endometrioma may be particularly detrimental to follicle reserve. An underutilized diagnostic procedure, transvaginal needle endoscopy with in-situ inspection after injection of saline suspension into the peritoneal cavity (hydrolaparoscopy) allows careful diagnosis of ovarian cortical pathology by colour changes from pearl-white to dark fibrotic. Thus, available evidence shows that expectant management may not be the best choice when an endometrioma is suspected: the delay in diagnosis causes delay in treatment and progression of the process leading to loss of follicles. On the contrary, early diagnosis through a minimally invasive technique, followed by early ablative surgery whenever indicated, represents the management of choice to preserve normal ovarian function., (Copyright © 2013 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The eutopic endometrium in women suffering from endometriosis is different in many ways from that of healthy controls. Both proliferative and secretory eutopic endometria exhibit changes in endometriosis with heterogeneous responses. In addition, nerve fibres appear in the endometrium and myometrium of these women. The endometrium is a rich source of pro-angiogenic factors and vascular events are often disrupted in endometriosis with an overall increase in angiogenesis. A number of investigations have shown that endometriosis is likely the most common cause of endometrial receptivity defects. Endometriosis is also associated with relative 17β-hydroxysteroid dehydrogenase type II deficiency and these molecular aberrations indicate that local oestrogen production sustains ectopic implants. Recently it has been shown that endometriosis, as a chronic inflammatory disorder, disrupts co-ordinated progesterone response throughout the reproductive tract, including the endometrium, leading to a condition of 'progesterone resistance'. Investigators have searched for biomarkers of endometriosis, but these investigations are fraught with methodological difficulties. In conclusion, molecular phenotyping of the endometrium is changing the disease paradigm, from being foremost an oestrogen-dependent disease to a disorder characterized primarily by progesterone resistance. In recent years, research on the pathogenesis of endometriosis has been focused on alterations in the uterus and particularly the eutopic endometrium. The eutopic endometrium in women suffering from endometriosis is different in many ways from that of healthy controls. Both proliferative and secretory eutopic endometria exhibit changes in endometriosis with heterogeneous responses. The endometrium is a rich source of pro-angiogenic factors and vascular events are often disrupted in endometriosis with an overall increase in angiogenesis. A number of investigations have shown that endometriosis is likely the most common cause of endometrial receptivity defects. Recently, it has been shown that endometriosis, as a chronic inflammatory disorder, disrupts co-ordinated progesterone response throughout the reproductive tract, including the endometrium, leading to a condition of 'progesterone resistance'. Investigators have searched for biomarkers of endometriosis, but these investigations are fraught with methodological difficulties. In conclusion, molecular phenotyping of the endometrium is changing the disease paradigm; from being foremost an oestrogen-dependent disease to a disorder characterized primarily by progesterone resistance., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Today an accurate diagnosis of adenomyosis can be made thanks to progress in imaging techniques: sonography and magnetic resonance imaging (MRI). This has made it possible to clinically correlate the presence of adenomyosis to infertility. At the same time, a series of pathogenetic hypotheses have been presented to explain this correlation. First, the identification of the myometrial junctional zone (JZ) and of its disruption and thickening has been linked to poor reproductive performance mainly through perturbed uterine peristalsis, a phenomenon that originates exclusively from the JZ in the nonpregnant uterus. In addition, a number of biochemical and functional alterations in both eutopic and heterotopic endometrium in women with adenomyosis have now been found to lead to lower receptivity, indicated by the presence of 'implantation marker' defects. In these patients there is also an altered decidualization and abnormal concentrations of intrauterine free radicals. All these abnormalities in the endometrial environment seem to contribute to subfertility. Several attempts have been made to restore fertility in adenomyosis patients, the oldest being gonadotrophin-releasing hormone agonists coupled to conservative surgery. Also, uterine artery embolization and MRI-assisted high-intensity focused ultrasound ablation have been tried with some degree of success., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The Roman Catholic Church reacted negatively to the announcement that the Nobel Prize for Medicine had been awarded to Robert G Edwards. Thirty-three years ago, Cardinal Albino Luciani, on the eve of his election to become Pope, stated that, whereas progress is certainly a beautiful thing, mankind has not always benefited from progress. Catholic criticism has raised seven points: (i) God wants human life to begin through the 'conjugal act' and not artificially; (ii) artificial interventions at the beginning of human life are dangerous and ethically unacceptable; (iii) limits can be imposed even upon an individual's freedom to achieve a legitimate goal, such as having a child within marriage; (iv) the massive loss of preimplantation embryos characterizing IVF must be considered as a tragic loss of 'nascent' human persons; (v) Edwards bears a moral responsibility for all subsequent developments in assisted reproduction technology and for all 'abuses' made possible by IVF; (vi) there can be deleterious consequences for offspring of assisted reproduction technology; and (vii) Edwards' discovery did not eliminate the causes of infertility. This article elaborates from the Roman Catholic perspective on each of these points, some of which are found to be more substantial than others., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

For decades, the Roman Catholic Church opposed use of condoms to prevent spread of sexually transmitted infections (STI) because of their contraceptive effect. In 2009, Pope Benedict XVI said that widespread use of condoms could worsen the situation, a position rejected as 'unscientific'. Recently, however the Pontiff stated that because the Church considers acts of prostitution and homosexuality to be gravely immoral and disordered, in such specific cases use of a condom might become an initial step in the direction of a moralization leading to an assumption of responsibility and a new awareness of the meaning of sexuality. In doing so, he reaffirmed his belief that condoms cannot solve the problem of STI spread, stressing the Church's position that modern societies no longer see sexuality as an 'expression of love, but only as a sort of drug that people administer to themselves'. The new Papal position has been widely applauded, but made conservative Catholics unhappy. A dialogue with the Church now seems possible: Does concentrating on condoms hinder the effectiveness of other strategies? What are the respective roles of condoms and other approaches to prevent infection spread? Does a special situation exist in Africa requiring specific and focused interventions?, (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Information on early embryo wastage is relevant for debating the status of human embryos. Two main points of view confront each other. Theists hold that human embryos should be treated as human persons from the moment of conception because, even accepting that human beings are the fruit of evolution, they are part of a divine project. Without a developmental event prior to which the human embryo could not be considered a human being, embryos should be regarded as if they were human subjects. After all, if one believes in the resurrection of the dead, it makes no difference at what stage one's life ends. Secularists oppose the idea of granting absolute value to human life from its beginning because early human embryos lack individuality and sentience. Personifying embryos is morally absurd because it would mean that countless human beings never had even the slightest chance to express their potential and, in the light of this catastrophic loss, one would expect early pregnancy wastage to have become an important research priority; this is not the case. In practical terms, most Western countries have legalized first-trimester abortion, de facto giving embryos a lower status than that of full person., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Establishing the proportion of fertilized oocytes and early human embryos that proceed to term may help policy makers in their evaluation of when the life of a new human individual begins and in determining the nature of protection to be accorded to it. The rate of spontaneous abortions, although increasing with age, overall does not exceed 15%. However, abortion rates refer only to 'clinical pregnancy', whereas early embryonic loss is more common than generally believed. Evidence of such wastage comes from many sources. Human fecundity rarely exceeds 35% and may be decreasing due to deterioration in semen quality. Embryological studies show that 50% of randomly recovered preimplantation embryos have severe anomalies. The study of sensitive markers of pregnancy, such as human chorionic gonadotrophin, indicates early embryo wastage in the order of 50%. Pregnancy wastage may be a function of the time lapse between ovulation and implantation as the implantation window extends between menstrual cycle days 20 and 24. Finally, data obtained with natural IVF cycles also indicate major losses, with an overall pregnancy rate of 7.2% per cycle and 15.8% per transfer. These data, however, are biased by a high cancellation rate and low oocyte retrieval in natural IVF cycles., (Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

On 8 May 2009, the Italian Constitutional Court declared, at least in part, that the law regulating assisted reproduction technology in Italy (Law 40/04) is unconstitutional. The most important theoretical point made by the Court is that the law does not provide unlimited protection to embryos, since it admits that some of them may not produce a viable fetus. Embryo protection is therefore limited by the imperative to ensure a concrete possibility to achieve a successful pregnancy. The Court also reaffirmed the need to empower the attending physician with the means to carry out a full evaluation. At present, the situation is not clear and, theoretically, requires a new intervention by Parliament. This, however, is unlikely., (Copyright 2009 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Human sexuality has multiple meanings, although reproduction is considered the focus of sexual activity. In spite of this, human sexuality began to lose its exclusive reproductive meaning very early in the evolution of the genus Homo and, with a concealed ovulation and a female accessible to the male during the entire menstrual cycle, the need became that of avoiding, rather than seeking conception during intercourse. The 'contraceptive revolutions' of the 20th century (sex without reproduction, reproduction without sex, reproduction in menopause and, one day, reproduction without gametes) are having a major impact on the lives of individual couples and women. At the same time, this tumultuous progress drew the attention of religious moralists, since ethics have always focused on sexuality and its moral regulation. Catholic ethicists have been at the forefront of the battle against 'dehumanizing' the reproductive process, whereas Judaism took a much more open position. Early Christian teaching on sexuality, focused on abstinence; this is because Christ himself defined celibacy as a better life choice for human beings. Drawing on this basis, early Church fathers developed the concept, upheld until the 20th century, that intercourse is totally justifiable only in order to procreate. Today, some cautious overtures are being made and the Church has recognized that sexuality can be expression of conjugal love independent from procreation.

Modern imaging techniques allow non-invasive diagnosis of adenomyosis, a relatively common disorder characterized by the presence of heterotopic endometrial glands and stroma in the myometrium with hyperplasia of the adjacent smooth muscle. The study of adenomyosis is greatly hampered by a lack of clear terminology and the absence of a consensus classification of the lesions. Any classification of adenomyosis must begin with an evaluation of the myometrium underlying the endometrium, the so-called junctional zone, since homogeneous thickening of this zone has become the standard criterion for non-invasive diagnosis. Although transvaginal sonography is useful for the detection of adenomyosis, the technique is highly operator dependent. Magnetic resonance imaging provides superior soft tissue resolution and currently represents the most accurate technique for non-invasive diagnosis. Adenomyosis represents a spectrum of lesions, ranging from increased thickness of the junctional zone to overt adenomyosis and adenomyomas, which in turn can be subclassified. It is increasingly recognized that adenomyosis is often associated with pelvic endometriosis yet the contribution of myometrial lesions to clinical symptoms, such as infertility and pain, remains poorly understood. Moreover, recent studies indicate that adenomyosis is a progressive disease that changes in appearance during the reproductive years. A consensus classification of uterine adenomyosis is urgently required.

Reproductive strategies for the human species have basically remained unaltered since Homo sapiens first appeared, probably in the valleys of Africa: males have always attempted to pass their genes to the largest feasible number of females, selecting those females capable of providing the best quality of oocytes; females invariably have sought a male capable of providing the best means of survival for herself and her offspring. This meant that human sexuality has been essentially conceptive, although it is reasonable to suppose that it began to lose this 'exclusive' connotation early in the cultural evolution of the species. Then, during the 20th century, major revolutions occurred: first, with the advent of contraception, sex without reproduction became a reality; then, with assisted reproduction technology, humans devised reproduction without sex; finally, very recently, women have begun to reproduce even in menopause. Additional strategies will, no doubt, soon be available, although we cannot as yet clearly see whether, or when, reproduction without sex and gametes, or in-vitro gestations will become available.

This paper attempts to provide a global perspective of the menopause as a period in a woman's life. It is growing in length, year after year and there is a need to place these years in the overall context of ageing. There are many fallacies about ageing. The most serious is the view describing old people exclusively as a burden for society, when in fact they can and should be considered as a resource. Women live longer almost everywhere in the world. Growing evidence indicates that the process of ageing differs in a considerable way in the two sexes. This difference may, at least in part, be due to sex-related differences in the regulation of stress response mediators. In addition, variability in the mitochondrial genome also displays a sex-specific impact on longevity. Restricting the discussion to longevity in the female, a paramount role must be given to sex hormones in improving a woman's ageing. Indeed, it is the fall in oestradiol production that qualitatively changes the ageing perspective in the human female, since oestrogen secretion plays a major role in guaranteeing a woman's psycho-physical equilibrium during the fertile period. These considerations represent the philosophical basis for post-menopausal hormone replacement therapy.