Archimetrosis: the evolution of a disease and its extant presentation : Pathogenesis and pathophysiology of archimetrosis (uterine adenomyosis and endometriosis).

PURPOSE: This article presents a novel concept of the evolution and, thus, the pathogenesis of uterine adenomyosis as well as peritoneal and peripheral endometriosis. Presently, no unifying denomination of this nosological entity exists. METHODS: An extensive search of the literature on primate evolution was performed. This included comparative functional morphology with special focus on the evolution of the birthing process that fundamentally differs between the haplorrhine primates and most of the other eutherian mammals. The data were correlated with the results of own research on the pathophysiology of human archimetrosis and with the extant presentation of the disease. RESULTS: The term Archimetrosis is suggested as a denomination of the nosological entity. Archimetrosis occurs in human females and also in subhuman primates. There are common features in the reproductive process of haplorrhine primates such as spontaneous ovulation and corpus luteum formation, spontaneous decidualization and menstruation. These have fused Müllerian ducts resulting in a uterus simplex. Following a usually singleton pregnancy, the fetus is delivered in the skull position. Some of these features are shared by other mammals, but not in that simultaneous fashion. In haplorrhine primates, with the stratum vasculare, a new myometrial layer has evolved during the time of the Cretaceous-Terrestrial Revolution (KTR) that subserves expulsion of the conceptus and externalization of menstrual debris in non-conceptive cycles. Hypercontractility of this layer has evolved as an advantage with respect to the survival of the mother and the birth of a living child during delivery and may be experienced as primary dysmenorrhea during menstruation. It may result in tissue injury by the sheer power of the contractions and possibly by the associated uterine ischemia. Moreover, the lesions at extra-uterine sites appear to be maintained by biomechanical stress. CONCLUSIONS: Since the pathogenesis of archimetrosis is connected with the evolution of the stratum vasculare, tissue injury and repair (TIAR) turns out to be the most parsimonious explanation for the development of the disease based on clinical, experimental and evolutionary evidence. Furthermore, a careful analysis of the published clinical data suggests that, in the risk population with uterine hypercontractility, the disease develops with a yet to be defined latency phase after the onset of the biomechanical injury. This opens a new avenue of prevention of the disease in potentially affected women that we consider to be primarily highly fertile.

[Evidence-based Facts of non-hormonal treatment of menopausal symptom]. / «Hard Facts¼ bei der nicht-hormonalen Therapie des klimakterischen Syndroms.

Evidence-based Facts of non-hormonal treatment of menopausal symptom Abstract. Menopausal symptoms like hot flushes and night sweats can have a great impact on quality of life. As first line, hormonal therapy with estrogens in combination with progestins is used, and shows beneficial effects on these symptoms. Some women, however, have contraindications against hormonal therapy or do not wish to take hormones at all. In these women, alternative treatments are needed to treat vasomotor symptoms. Pharmacologic substances like antidepressants, anticonvulsants or antihypertensive drugs show a significant reduction of these symptoms in menopausal women. Phytopharmaceutical products may show beneficial effects but study designs often do not fulfil strict scientific criteria. Furthermore, dosage and composition of the products may differ considerably. Best data are available for isoflavons and extracts of cimicifuga racemosa. Other alternative therapies like yoga, exercise, hypnosis and acupuncture showed promising results in small studies and may be recommended individually.

Perimenopause and Postmenopause - Diagnosis and Interventions. Guideline of the DGGG and OEGGG (S3-Level, AWMF Registry Number 015-062, September 2020).

Aim The aim of the interdisciplinary S3-guideline Perimenopause and Postmenopause - Diagnosis and Interventions is to provide help to physicians as they inform women about the physiological changes which occur at this stage of life and the treatment options. The guideline should serve as a basis for decisions taken during routine medical care. This short version lists the statements and recommendations given in the long version of the guideline together with the evidence levels, the level of recommendation, and the strength of consensus. Methods The statements and recommendations are largely based on methodologically high-quality publications. The literature was evaluated by experts and mandate holders using evidence-based medicine (EbM) criteria. The search for evidence was carried out by the Essen Research Institute for Medical Management (EsFoMed). To some extent, this guideline also draws on an evaluation of the evidence used in the NICE guideline on Menopause and the S3-guidelines of the AWMF and has adapted parts of these guidelines. Recommendations Recommendations are given for the following subjects: diagnosis and therapeutic interventions for perimenopausal and postmenopausal women, urogynecology, cardiovascular disease, osteoporosis, dementia, depression, mood swings, hormone therapy and cancer risk, as well as primary ovarian insufficiency.

Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020).

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to women's individual needs, take account of her personal circumstances, and have few or no side effects.

Survey of Third-Party Parenting Options Associated With Fertility Preservation Available to Patients With Cancer Around the Globe.

Purpose: In the accompanying article, "Survey of Fertility Preservation Options Available to Patients With Cancer Around the Globe," we showed that specific fertility preservation services may not be offered at various sites around the world because of cultural and legal barriers. We assessed global and regional experiences as well as the legal status of third-party reproduction and adoption to serve as a comprehensive international data set and resource for groups that wish to begin oncofertility interventions. Methods: We provide data on the legalities of third-party assisted reproductive technologies and other family-building options in the 28 oncofertility-practicing countries surveyed. Results: We found regional and country differences that will be important in the development of tailored resources for physicians and for patient brochures that are sensitive to these local restrictions and cultural norms. Conclusion: Because many patients first consult Web-based materials, the formal assessment of the availability of these options provides members of the global oncofertility community with data to which they might otherwise not have ready access to better serve their patients.

Survey of Fertility Preservation Options Available to Patients With Cancer Around the Globe.

Purpose: Oncofertility focuses on providing fertility and endocrine-sparing options to patients who undergo life-preserving but gonadotoxic cancer treatment. The resources needed to meet patient demand often are fragmented along disciplinary lines. We quantify assets and gaps in oncofertility care on a global scale. Methods: Survey-based questionnaires were provided to 191 members of the Oncofertility Consortium Global Partners Network, a National Institutes of Health-funded organization. Responses were analyzed to measure trends and regional subtleties about patient oncofertility experiences and to analyze barriers to care at sites that provide oncofertility services. Results: Sixty-three responses were received (response rate, 25%), and 40 were analyzed from oncofertility centers in 28 countries. Thirty of 40 survey results (75%) showed that formal referral processes and psychological care are provided to patients at the majority of sites. Fourteen of 23 respondents (61%) stated that some fertility preservation services are not offered because of cultural and legal barriers. The growth of oncofertility and its capacity to improve the lives of cancer survivors around the globe relies on concentrated efforts to increase awareness, promote collaboration, share best practices, and advocate for research funding. Conclusion: This survey reveals global and regional successes and challenges and provides insight into what is needed to advance the field and make the discussion of fertility preservation and endocrine health a standard component of the cancer treatment plan. As the field of oncofertility continues to develop around the globe, regular assessment of both international and regional barriers to quality care must continue to guide process improvements.

Creating a Global Community of Practice for Oncofertility.

Fertility preservation in the cancer setting, known as oncofertility, is a field that requires cross-disciplinary interaction between physicians, basic scientists, clinical researchers, ethicists, lawyers, educators, and religious leaders. Funded by the National Institutes of Health, the Oncofertility Consortium (OC) was formed to be a scientifically grounded, transparent, and altruistic resource, both intellectual and monetary, for building this new field of practice capable of addressing the unique needs of young patients with cancer. The OC has expanded its attention to include other nonmalignant conditions that can threaten fertility, and the work of the OC now extends around the globe, involving partners who together have created a community of shared effort, resources, and practices. The OC creates materials that are translated, disseminated, and amended by all participants in the field, and local programs of excellence have developed worldwide to accelerate the pace and improve the quality of oncofertility research and practice. Here we review the global oncofertility programs and the capacity building activities that strengthen these research and clinical programs, ultimately improving patient care.

Bidirectional interaction between oral contraception and lamotrigine in women with epilepsy - Role of progestins.

PURPOSE: To investigate the effects of various progestins in combined oral contraceptives (COCs) on lamotrigine (LTG) serum concentrations and, vice versa, the potential impact of LTG on progestin serum levels during the menstrual cycle. METHODS: Twenty women with epilepsy (WWE) undergoing LTG monotherapy and COC (LTG group; mean ± SD [median; range] age 24.2 ± 4.6 [23.0; 18-37] years) as well as fourteen controls on COC (24.9 ± 5.6 [22.5; 20-39] years) were assessed for eligibility and all agreed to participate in the study and remained for data analyses. RESULTS: LTG levels differed significantly between phases of inactive pill and active pill use (p= 0.004), particularly with drospirenon (p= 0.018) and levonorgestrel (p= 0.068) as progestogen component but not with gestoden (p= 0.593). Furthermore, the LTG group showed significantly lower progestin levels during inactive pill when compared to active pill use with respect to levonorgestrel (p= 0.042) and drospirenon (p= 0.018) but not to gestoden (p= 0.109). Progestin concentrations did not differ between patients and controls (p> 0.05). CONCLUSIONS: The findings suggest that drospirenon and levonorgestrel but not gestoden seem to reduce LTG serum concentrations when being co-administered in WWE which might be of importance concerning seizure risk. Vice versa, no effect of LTG on several progestins could be demonstrated, arguing against a potential loss of contraception safety with LTG.

Diagnosis and Therapy Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 1, Basic Assessment of the Woman.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German/Austrian/Swiss interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. This guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aims One third of the causes of involuntary childlessness are still unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. At present, there is no standard treatment concept, as currently no standard multidisciplinary procedures exist for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnostic workup and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations The first part of this guideline focuses on the basic assessment of affected women, including standard anatomical and endocrinological diagnostic procedures and examinations into any potential infections. Other areas addressed in this guideline are the immunological workup with an evaluation of the patient's vaccination status, an evaluation of psychological factors, and the collection of data relating to other relevant factors affecting infertility. The second part will focus on explanations of diagnostic procedures compiled in collaboration with specialists from other medical specialties such as andrologists, human geneticists and oncologists.

Diagnosis and Treatment Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 2, Hemostaseology, Andrology, Genetics and History of Malignant Disease.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German-language interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. The guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aim In one third of cases, the cause of involuntary childlessness remains unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. There is no standard treatment concept for these patients at present, as there are currently no standard multidisciplinary procedures for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnosis and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations This second part of the guideline describes the hematological workup for women as well as additional diagnostic procedures which can be used to investigate couples and which are carried out in cooperation with physicians working in other medical fields such as andrologists, geneticists and oncologists.

Opioids and reproduction.

More than 40years ago, the endogenous opioids were first described. Their role as important neuromodulators of pain and their influence on a variety of neuroendocrine control systems within the central nervous system has been recognized. More recently, endogenous opioids and their receptor have been identified in a variety of reproductive and non-reproductive tissues outside the central nervous system. What role the opioid system plays in these peripheral tissues and organs is not completely understood and thus the subjects of current research. In the central nervous system, endogenous opioids inhibit pulsatile Gonadotropin Releasing Hormone (GnRH) release, affecting the release of gonadotropins from the pituitary, and thus mediating stress response within the central nervous-pituitary-gonadal axes in both women and men-Peripherally, endogenous opioids have been demonstrated to be present-among other organs-in the pancreas and in the ovary, where they are produced by granulosa cells and may influence oocyte maturation. In men, endogenous opioids play a role in sperm production within the testis. Opioid antagonists such as naltrexone have been used to restore cyclicity in women through improvement in insulin resistance, GnRH-pulsatility and hyperandrogenemia stemming from specific pathophysiological conditions such as hypothalamic amenorrhea, polycystic ovarian syndrome, hyperinsulinemia, ovarian hyperstimulation syndrome. Opioid antagonists have also been used to treat male sexual disorders and male infertility. In summary, endogenous opioids exert a variety of actions within the reproductive system which are reviewed in this chapter.

Behavioural and neural responses to aversive visceral stimuli in women with primary dysmenorrhoea.

BACKGROUND: Chronic pelvic pain, in particular dysmenorrhoea, is a significant yet unresolved healthcare problem in gynaecology. As interoceptive sensitivity and underlying neural mechanisms remain incompletely understood, this functional magnetic resonance imaging (fMRI) study assessed behavioural and neural responses to visceral stimuli in primary dysmenorrhoea (PMD). METHODS: Women with PMD (N = 19) without psychological comorbidity and healthy women (N = 20) were compared with respect to visceral sensory and pain thresholds, and to neural responses to individually calibrated mildly painful and painful rectal distensions implemented during scanning. Trial-by-trial ratings of perceived intensity were accomplished with visual analogue scales (VAS). RESULTS: Although women with dysmenorrhoea reported significantly higher chronic pain intensity and pain interference with daily life activities (p < 0.01, assessed with the West Haven-Yale Multidimensional Pain Inventory), there were no differences between groups in visceral sensitivity and mean trial-by-trial VAS ratings were virtually identical. Analysis of neural responses revealed activation in brain regions previously shown to be involved in the processing of visceral stimuli with differences between painful and mildly painful stimulation, but no group differences were found even when using a liberal statistical threshold. CONCLUSIONS: Dysmenorrhoea patients show unaltered perceptual and neural responses to experimental interoceptive stimuli. Despite limited sample size, these negative results argue against a generalized sensitization towards interoceptive stimuli in patients without psychological comorbidities. Future studies should clarify the role of psychosocial factors in central sensitization using more pain region-specific models in larger and clinically more heterogeneous samples. SIGNIFICANCE: Despite higher chronic pain and pain interference with daily life activities, women with primary dysmenorrhoea do not differ from healthy women with respect to visceral sensitivity or neural processing of aversive interoceptive stimuli induced by rectal distensions. Generalized sensitization may be present only in subgroups with pronounced psychosocial or psychiatric disturbances.

Beta endorphin in serum and follicular fluid of PCOS- and non-PCOS women.

PURPOSE: To compare the concentrations of beta endorphin in serum and follicular fluid (FF) of PCOS- and non-PCOS women. Secondarily, to investigate associations between beta endorphin and other parameters. METHODS: Fifty-nine women undergoing in vitro fertilization (IVF) were included in the study. Sixteen were stratified to the PCOS group using the Rotterdam criteria. The remaining 43 women served as controls. Follicular fluid was collected during oocyte retrieval and peripheral blood sampling was performed on the same day. Beta endorphin concentrations in serum and follicular fluid, serum levels of insulin, glucose, LH, estradiol and progesterone were measured. Additionally, testosterone was measured before starting the stimulation protocol. RESULTS: There was no difference in beta endorphin levels between PCOS- and non-PCOS women. The concentration of the peptide was higher in serum than in FF, likely due to collection of FF after ovulation induction and corresponding to the early luteal phase. We found a significant correlation between the number of mature Metaphase II (MII) oocytes retrieved and beta endorphin concentration in FF. In women with biochemical hyperandrogenemia, beta endorphin levels in FF correlated with testosterone levels. CONCLUSION: Beta Endorphin concentrations in serum and FF do not differ between PCOS- and non PCOS-women undergoing IVF. However, together with sex hormones, beta endorphin might play a key role in oocyte maturation.

Impact of the opioid system on the reproductive axis.

Endogenous opioids, first described more than 40 years ago, have long been recognized for their main role as important neuromodulators within the central nervous system. More recently endogenous opioids and their receptor have been identified in a variety of reproductive and nonreproductive tissues outside the central nervous system. Their role within these tissues and organs, however, is only incompletely understood. In the central nervous system, endogenous opioids inhibit pulsatile GnRH release, in part mediating the stress response within the central nervous-pituitary gonadal axis, resulting in hypothalamic amenorrhea. In the ovary, the presence of endogenous opioids primarily produced by granulosa cells has been demonstrated within the follicular fluid, likely influencing oocyte maturation. In hypothalamic amenorrhea, normal cycles can be restored by the administration of opioid antagonists, such as naltrexone. In polycystic ovarian syndrome, endogenous opioids have found to be elevated and may stimulate insulin secretion from the endocrine pancreas. This effect can be inhibited by opioid antagonists, resulting in a decrease of circulating insulin levels in response to glucose challenge. Endogenous opioids may also play a role in the pathogenesis of ovarian hyperstimulation syndrome. In summary, endogenous opioids exert a wide variety of actions within the reproductive system and are worthy of further scientific study.

What is new in 2017? Update on fertility preservation in cancer patients.

The prevention of fertility loss due to cancer treatment as well as non-malignant causes has been gaining importance over the last few decades. Clinically applied modalities for fertility preservation in cancer patients include cryopreservation of oocytes and embryos, the application of GnRH agonists, ovarian tissue banking, and cryopreservation of ejaculated or surgically extracted sperm. In addition, several new possibilities to restore fertility are currently being investigated, such as the establishment of in-vitro culture systems for gonadal tissue, the development of artificial gonads, and the application of germline stem cells. This review aims to provide an update on the methods currently applied in clinical practice for fertility preservation, as well as to summarize the progress made in the development of novel strategies for fertility preservation.

Localization of TrkB and p75 receptors in peritoneal and deep infiltrating endometriosis: an immunohistochemical study.

BACKGROUND: The roles of the neurotrophins NGF (Neurotrophic growth factor) and BDNF (brain-derived neurotrophic factor) in neuronal growth and development are already known. Meanwhile, the neurotrophin receptors TrkA (tropomyosin related kinase A), TrkB, and p75 are important for determining the fate of cells. In endometriosis, this complex system has not been fully elucidated yet. The aim of this study was to evaluate the expression and location of these neurotrophins and their receptors in peritoneal (PE) and deep infiltrating endometriotic (DIE) tissues and to measure and compare the density of nerve fibers in the disease subtypes. METHODS: PE lesions (n = 20) and DIE lesions (n = 22) were immunostained and analyzed on serial slides with anti-BDNF, -NGF, -TrkA, -TrkB, -p75,-protein gene product 9.5 (PGP9.5, intact nerve fibers) and -tyrosine hydroxylase (TH, sympathetic nerve fibers) antibodies. RESULT: There was an equally high percentage (greater than 75 %) of BDNF-positive immunostaining cells in both PE and DIE. TrkB (major BDNF receptor) and p75 showed a higher percentage of immunostaining cells in DIE compared to in PE in stroma only (p < 0.014, p < 0.027, respectively). Both gland and stroma of DIE lesions had a lower percentage of NGF-positive immunostaining cells compared to those in PE lesions (p < 0.01 and p < 0.01, respectively), but there was no significant reduction in immunostaining of TrkA in DIE lesions. There was no difference in the mean density of nerve fibers stained with PGP9.5 between PE (26.27 ± 17.32) and DIE (28.19 ± 33.15, p = 0.8). When we performed sub-group analysis, the density of nerves was significantly higher in the bowel DIE (mean 57.33 ± 43.9) than in PE (mean 26.27 ± 17.32, p < 0.01) and non-bowel DIE (mean 14.6. ± 8.6 p < 0.002). CONCLUSIONS: While the neurotrophin BDNF is equally present in PE and DIE, its receptors TrkB and p75 are more highly expressed in DIE and may have a potential role in the pathophysiology of DIE, especially in promotion of cell growth. BDNF has a stronger binding affinity than NGF to the p75 receptor, likely inducing sympathetic nerve axonal pruning in DIE, resulting in the lower nerve fiber density seen.

Follicular growth after xenotransplantation of cryopreserved/thawed human ovarian tissue in SCID mice: dynamics and molecular aspects.

PURPOSE: To study the influence of xenotransplantation on follicular recruitment and growth in cryopreserved/thawed human ovarian tissue. METHOD: Two 3-mm pieces of cryopreserved/thawed human ovarian tissue obtained from female cancer patients (n = 11) were xenotransplanted into a subcutaneous neck pouch of 6-week-old ovarectomized SCID mice (n = 33) for 4 (n = 18) and 12 (n = 15) weeks. RESULT: Thirty-two out of 33 mice survived the entire observation periods. Graft recovery rate was 95.58 % (65 of 68 grafts). The percentages of primordial follicles after 4 weeks (P < 0.001) and 12 weeks (P = 0.009) of grafting were significantly lower in comparison to pregraft controls. The percentage of secondary follicle was significantly higher after 4 weeks of grafting (P = 0.018) and after 12 weeks (P = 0.001) of grafting in comparison to pregraft controls. Ki67 immunohistochemistry showed that proliferative follicles were significantly higher after 4 and 12 weeks of grafting compared to pregraft controls (P < 0.001). All follicles analyzed by TUNEL staining appeared healthy after xenotransplantation. The expression level of PTEN was reduced by 2.47-fold after 4 weeks of xenotransplantation, and this result was significant when 2-ΔCt were analyzed (P = 0.042). CONCLUSION: The higher proportion of growing follicles compared to resting follicles observed after xenotransplantation is most likely due to downregulation of PTEN gene expression followed by acceleration of follicular recruitment.