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INTRODUCTION: Peritoneal infiltrating and fibrotic endometriosis, also known as deep endometriosis, is the most severe manifestation of the disease that can cause severe complications including bowel and ureteral stenosis. The natural history of these lesions and the possible effect of hormonal treatments on their progression are undefined. Therefore, we conducted a systematic review and meta-analysis to investigate whether and how frequently deep endometriosis progresses over time without or with ovarian suppression. This could inform management decisions in asymptomatic and mildly symptomatic patients. MATERIAL AND METHODS: For this pre-registered systematic review (CRD42023463518), the PubMed and Embase databases were screened, and studies published between 2000 and 2023 that serially evaluated the size of deep endometriotic lesions without or with hormonal treatment were selected. Data on the progression, stability, or regression of deep endometriotic lesions were recorded as absolute frequencies or mean volume variations. Estimates of the overall percentage of progression and corresponding 95% confidence intervals were calculated using a random-effect model. When studies reported lesion progression as pre- and post-treatment volume means, the delta of the two-volume means was calculated and analyzed using the inverse variance method. RESULTS: A total of 29 studies were identified, of which 19 studies with 285 untreated and 730 treated patients were ultimately selected for meta-analysis. The overall estimate of the percentage of lesion progression in untreated individuals was 21.4% (95% CI, 6.8-40.8%; I2 = 90.5%), whereas it was 12.4% during various hormonal treatments (95% CI, 9.0-16.1%; I2 = 0%). Based on the overall meta-analysis estimates, the odds ratio of progression in treated vs untreated patients was 0.52 (95% CI, 0.41-0.66). During hormonal suppression, the mean volume of deep endometriotic lesions decreased significantly by 0.87 cm3 (95% CI, 0.19-1.56 cm3; I2 = 0%), representing -28.5% of the baseline volume. CONCLUSIONS: Untreated deep endometriotic lesions progressed in about one in five patients. Medical therapy reduced but did not eliminate this risk. Given the organ function failure potentially caused by these lesions, the decision whether to use hormonal treatments in asymptomatic or mildly symptomatic women should always be shared, carefully weighing the potential benefits and harms of the two alternatives after extensive counseling.
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Progressão da Doença , Endometriose , Humanos , Endometriose/tratamento farmacológico , Endometriose/patologia , Feminino , Antagonistas de Hormônios/uso terapêuticoRESUMO
OBJECTIVE: To evaluate whether laser-mediated assisted hatching (AH) performed on vitrified/warmed blastocysts before embryo transfer can improve live birth rate. DESIGN: The "pArtiaL zonA pelluciDa removal by assisteD hatchINg of blastocysts (ALADDIN)" is a 2-center comparative study with a parallel randomized controlled design. SETTING: University hospital. PATIENTS: Participants were recruited between September 2018 and November 2021. They were aged 18-39 years, underwent nondonor in vitro fertilization cycles, and were scheduled for elective single embryo transfer with vitrified/warmed blastocysts. Those with uterine abnormalities, body mass index of >35 kg/m2, severe male factor infertility, or performing preimplantation genetic testing were excluded. INTERVENTION: Assisted hatching was performed using a 1,480 nm diode laser, removing approximately one-third of the zona pellucida with continuous 0.2 ms pulses applied from the 1-5 o'clock positions. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate. Secondary end points included clinical pregnancy, miscarriage, multiple pregnancies, preterm births, obstetric and neonatal complications, and congenital anomalies. RESULTS: Overall, 698 participants met the inclusion criteria and were randomized: 352 patients were assigned to the AH arm and 346 to the control arm. Of the participants, 105 (29.8%) and 101 (29.2%), respectively, achieved a live birth after treatment. The relative risk of live birth in patients with vitrified/warmed blastocysts treated with AH was 1.02 (95% confidence interval, 0.86-1.19). Exploratory subgroup analyses for women's age, recruiting centers, indications for in vitro fertilization, method of insemination, blastocyst quality, and days of blastocyst development failed to highlight any clinical situation that could benefit from AH in thawed blastocysts. CONCLUSION: In patients undergoing frozen embryo transfer with vitrified/warmed blastocysts, laser AH does not improve the live birth rate. Further studies are required to rule out milder but potentially interesting benefits in specific subgroups of patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03623659.
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Blastocisto , Nascido Vivo , Taxa de Gravidez , Vitrificação , Humanos , Feminino , Adulto , Gravidez , Criopreservação/métodos , Zona Pelúcida , Adulto Jovem , Fertilização in vitro/métodos , Infertilidade/terapia , Infertilidade/fisiopatologia , Infertilidade/diagnóstico , Adolescente , Transferência Embrionária/métodos , Transferência Embrionária/efeitos adversos , Resultado do Tratamento , Técnicas de Cultura Embrionária , Transferência de Embrião Único/métodos , Transferência de Embrião Único/efeitos adversos , Lasers , MasculinoAssuntos
Adenomiose , Endometriose , Infertilidade Feminina , Feminino , Humanos , Endometriose/complicações , Endometriose/diagnóstico , Adenomiose/complicações , Adenomiose/diagnóstico , Jardins , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/etiologia , Infertilidade Feminina/terapiaRESUMO
According to consistent epidemiological data, the slope of the incidence curve of endometriosis rises rapidly and sharply around the age of 25 years. The delay in diagnosis is generally reported to be between 5 and 8 years in adult women, but it appears to be over 10 years in adolescents. If this is true, the actual onset of endometriosis in many young women would be chronologically placed in the early postmenarchal years. Ovulation and menstruation are inflammatory events that, when occurring repeatedly for years, may theoretically favour the early development of endometriosis and adenomyosis. Moreover, repeated acute dysmenorrhoea episodes after menarche may not only be an indicator of ensuing endometriosis or adenomyosis, but may also promote the transition from acute to chronic pelvic pain through central sensitization mechanisms, as well as the onset of chronic overlapping pain conditions. Therefore, secondary prevention aimed at reducing suffering, limiting lesion progression, and preserving future reproductive potential should be focused on the age group that could benefit most from the intervention, i.e. severely symptomatic adolescents. Early-onset endometriosis and adenomyosis should be promptly suspected even when physical and ultrasound findings are negative, and long-term ovulatory suppression may be established until conception seeking. As nowadays this could mean using hormonal therapies for several years, drug safety evaluation is crucial. In adolescents without recognized major contraindications to oestrogens, the use of very low-dose combined oral contraceptives is associated with a marginal increase in the individual absolute risk of thromboembolic events. Oral contraceptives containing oestradiol instead of ethinyl oestradiol may further limit such risk. Oral, subcutaneous, and intramuscular progestogens do not increase the thromboembolic risk, but may interfere with attainment of peak bone mass in young women. Levonorgestrel-releasing intra-uterine devices may be a safe alternative for adolescents, as amenorrhoea is frequently induced without suppression of the ovarian activity. With regard to oncological risk, the net effect of long-term oestrogen-progestogen combinations use is a small reduction in overall cancer risk. Whether surgery should be considered the first-line approach in young women with chronic pelvic pain symptoms seems questionable. Especially when large endometriomas or infiltrating lesions are not detected at pelvic imaging, laparoscopy should be reserved to adolescents who refuse hormonal treatments or in whom first-line medications are not effective, not tolerated, or contraindicated. Diagnostic and therapeutic algorithms, including self-reported outcome measures, for young individuals with a clinical suspicion of early-onset endometriosis or adenomyosis are proposed.
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Adenomiose , Dor Crônica , Endometriose , Adulto , Adolescente , Feminino , Humanos , Endometriose/diagnóstico , Endometriose/prevenção & controle , Adenomiose/diagnóstico , Adenomiose/prevenção & controle , Prevenção Secundária , Dismenorreia , Dor Pélvica/etiologia , Dor Pélvica/prevenção & controle , Dor Pélvica/tratamento farmacológico , Anticoncepcionais Orais/uso terapêutico , Doença CrônicaRESUMO
The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.
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Adenomiose , Endometriose , Gravidez , Feminino , Adolescente , Humanos , Adulto , Endometriose/epidemiologia , Endometriose/prevenção & controle , Endometriose/complicações , Adenomiose/epidemiologia , Amenorreia/complicações , Prevenção Secundária , MenstruaçãoRESUMO
STUDY QUESTION: Is it possible to reduce the cost of GnRH agonist treatment for endometriosis by using non-standard dosing regimens? SUMMARY ANSWER: An extended-interval dosing regimen of a 3.75 mg depot formulation of triptorelin injected every 6 weeks instead of every 4 weeks reduces the cost by one-third without compromising the effect on pain relief. WHAT IS KNOWN ALREADY: Cost constitutes a limit to prolonged GnRH agonists use. Alternative modalities to reduce the economic burden of GnRH agonist treatment have been anecdotally attempted. STUDY DESIGN SIZE DURATION: A systematic review was conducted to evaluate and compare the effect of three alternative modalities for GnRH use in women with endometriosis, i.e. intermittent oestrogen deprivation therapy, reduced drug dosage, and extended-interval dosing regimens of depot formulations. A PubMed and Embase search was initially conducted in October 2022 and updated in January 2023 using the following search strings: (endometriosis OR adenomyosis) AND (GnRH-agonists OR gonadotropin-releasing hormone agonists OR triptorelin OR leuprorelin OR goserelin OR buserelin OR nafarelin). Full-length articles published in English in peer-reviewed journals since 1 January 1980, and reporting original data on GnRH agonist treatment of pain symptoms associated with endometriosis were selected. PARTICIPANTS/MATERIALS SETTING METHODS: Information was extracted on study design, GnRH-agonist used, dosage, total duration of therapy, side effects, treatment adherence, and pelvic pain relief. Reviews, commentaries, conference proceedings, case reports, and letters to the editor were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1664 records screened, 14 studies regarding clinical outcomes associated with the 3 considered alternative modalities for GnRH agonist use were eventually included (intermittent oestrogen deprivation therapy, n = 2; low-dose or 'draw-back' therapy, n = 8; extended-interval dosing regimen, n = 4). Six studies were randomized controlled trials (RCTs) (double blind, n = 2) and eight adopted a prospective cohort design (non-comparative, n = 6; comparative, n = 2). A total of 776 women with endometriosis were recruited in the above studies (intermittent oestrogen deprivation therapy, n = 77; low-dose or 'draw-back' therapy, n = 528; extended-interval dosing regimen, n = 171). Robust data demonstrating cost saving without detrimental clinical consequences were available for the extended-interval dosing regimen only. In particular, the 3.75 mg triptorelin depot preparation inhibits ovarian function for a longer period compared with the 3.75 mg leuprorelin depot preparation, allowing injections every 6 instead of 4 weeks. Based on the cost indicated by the Italian Medicine Agency for the 3.75 mg triptorelin depot preparation, this would translate in a yearly saving of 744.60 (2230.15-1485.55; -33.4%). LIMITATIONS REASONS FOR CAUTION: The quality of the evidence reported in the selected articles was not formally evaluated and a quantitative synthesis could not be performed. Some studies were old and the tested therapeutic approaches were apparently obsolete. Only cost containment associated with GnRH analogue use, and not cost-effectiveness, has been addressed. WIDER IMPLICATIONS OF THE FINDINGS: Consuming less resources without negatively impacting on health outcomes carries ethical and practical implications for individuals and the community, as this approach may result in overall increased healthcare access. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Italian Ministry of Health (Ricerca Corrente 2023, IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano). E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. REGISTRATION NUMBER: N/A.
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We performed a comprehensive narrative synthesis of systematic reviews with meta-analysis published in the last 5 years on the association of endometriosis and adenomyosis with reproductive and obstetric outcomes. This review aimed to define the information on which to base preconceptional counseling and clarify whether and in which cases pregnant women with endometriosis and adenomyosis should be referred to tertiary care centers and followed as high-risk obstetric patients. Reduced pregnancy and live birth rates and an increased miscarriage rate were observed in women with endometriosis and adenomyosis. The effect was larger in women with adenomyosis than in those with endometriosis. Women with superficial peritoneal and ovarian endometriosis do not appear to be at considerably increased risk of major obstetric and neonatal complications, whereas women with severe endometriosis, whether operated or not, are at several-fold increased risk of placenta previa. Moreover, deep infiltrating endometriosis is a risk factor for spontaneous hemoperitoneum in pregnancy and is associated with surgical complications at cesarean section. Overall, women with adenomyosis are at increased risk of various adverse obstetric outcomes, including preeclampsia, preterm delivery, fetal malpresentation, postpartum hemorrhage, low birth weight, and small for gestational age. Most studies included in the considered systematic reviews are characterized by substantial qualitative and quantitative heterogeneity. This makes a reliable assessment of the available evidence difficult, and caution should be exercised when attempting to derive clinical indications. Nevertheless, women with deep infiltrating endometriosis and severe adenomyosis should be considered at high obstetric risk and can benefit from referral to tertiary care centers where they can be safely followed through pregnancy and delivery. Whether the same should apply also to pregnant women with minimal endometriosis and adenomyosis forms is currently uncertain. Emerging evidence suggests that some adverse reproductive and obstetric outcomes observed in women with endometriosis are, in fact, associated with coexisting adenomyosis.
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Aborto Espontâneo , Adenomiose , Endometriose , Infertilidade , Recém-Nascido , Gravidez , Feminino , Humanos , Endometriose/complicações , Endometriose/diagnóstico , Endometriose/epidemiologia , Adenomiose/complicações , Adenomiose/diagnóstico , Adenomiose/epidemiologia , Cesárea/efeitos adversos , Revisões Sistemáticas como Assunto , Infertilidade/complicações , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Resultado da Gravidez/epidemiologiaRESUMO
With the implementation of COVID-19 vaccine up-take, doubts regarding the impact of immunization on future fertility have begun to emerge. We have examined vaccine safety on male reproductive health. We set up a multicentre (three infertility centers), retrospective study in order to assess semen parameters and fertilization rate of one hundred-six men in a pairwise comparison between the first and second assisted reproduction technology (ART) attempt, performed respectively before and after COVID-19 vaccination. Median time (range) between the first vaccine dose and the second ART cycle was 75 days (39-112). Semen parameters did not change before and after the exposure. Fertilization rate was also similar before and after vaccination. Twenty-five patients (24%) were oligozoospermic before the vaccination while 26 (25%) after the exposure (P = 0.87). Severe asthenozoospermia were present in 11 patients before as well as after the exposure. No difference was observed even after considering different types of vaccines (mRNA or viral vector). COVID-19 vaccination did not affect sperm quality and fertilization capacity of men undergoing ART treatments and should be considered safe for men's reproductive health.
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Vacinas contra COVID-19 , Saúde Reprodutiva , COVID-19 , Vacinas contra COVID-19/efeitos adversos , Humanos , Masculino , Estudos Retrospectivos , VacinaçãoRESUMO
INTRODUCTION: Endometriosis pathogenesis is still a matter of debate. It is now agreed that a complex cooperation of genetic, hormonal, immune and environmental factors is implicated. However, no consensus has been reached yet on what firstly is responsible for the initiation, promotion and survival of endometrial-like tissue outside the uterine cavity. Since consistent evidence have found immunological alterations in women with the disease, the impairment of immune system has been considered for decades one of the possible causes of endometriosis. The aim of this literature review is to summarize the available findings on a particular aspect of this topic represented by the inhibition of natural killer (NK) cell activity in women affected as a paradigmatic example of the complexity in studying the pathogenesis of endometriosis. EVIDENCE ACQUISITION: Advanced search of PubMed for English articles published between 1990 and September 2020 using the keywords "endometriosis" or "endometrioma" or "endometriotic" or "ectopic endometrium" in combination with "natural killer cells" (NK). EVIDENCE SYNTHESIS: Consistent studies have found an impairment in NK cell activity in women with endometriosis especially in advanced stages of disease (stage III/IV). Reports to explain these findings support the phenomenon as a consequence of the disease establishment. Evidence from genetic studies have questioned the role of these dysfunctions in the pathogenesis of the disease. CONCLUSIONS: Immunological dysfunctions and the decreased NK cell cytotoxicity may only represent consequence of endometriosis, although the underlining mechanisms still need to be elucidated.