Proposal for a descriptive and differentiated presentation of the longitudinal impact of the new organized cancer screening guideline and HPV vaccination in Germany.

INTRODUCTION: Since 01/01/2020, the cervical cancer screening in Germany has been carried out due to the organized early cancer diagnosis guideline (oKFE-RL). In 2007, HPV vaccination was initiated in Germany. The main goal of both initiatives is to further reduce the incidence of invasive cervical cancer. To assess the effect of the new screening strategy in a timely manner, monitoring of short-term changes need to be considered. Ideally, the effects of both prevention methods would be presented together in one model. MATERIALS AND METHODS: Because no change in the incidence of invasive cervical cancer is initially expected, the incidence of CIN 3 is used as a surrogate parameter to assess the effects of the prevention efforts. Based on expected additional effects of vaccination and co-testing, a model-based estimation of the expected CIN 3 incidence during the evaluation of the screening program is performed using the CIN 3 incidence in the Saarland population. MODELING RESULTS: The oKFE-RL provides for two groups: Primary cytodiagnosis continues until 35 years of age. Here, in the next few years, CIN 3 incidence will be reduced not by the oKFE-RL but by the increasing proportion of vaccinated women. In the group over 35 years, co-testing was introduced with a stringent algorithm. Due to the higher sensitivity of the HPV test, significantly more CIN 3 are detected in the first round of 3 years and thus, the CIN 3 incidence initially increases. As these CIN 3 are absent in the second round, significantly fewer CIN 3 cases will be detected then. These effects suggest a global decrease in CIN 3 incidence of 25.8% after 6 years. CONCLUSION: Observation of the age distribution curve of CIN 3 allows both effects of prevention to be assessed in a timely manner and separately. In the future, data from epidemiologic cancer registries should be incorporated into the model to replace modeling with real data.

[Hormone replacement therapy in peri- and postmenopause]. / Hormontherapie in der Peri- und Postmenopause.

Peri- and postmenopausal disorders can have a significant impact on quality of life. Hormone replacement therapy (HRT) might be necessary in order to decrease women's symptoms. The German S3 guideline "Peri- and Postmenopause-Diagnostics and Therapy" (2020) provides recommendations that include the most recent evidence as well as the Women's Health Initiative (WHI) study results from 2002 and 2004. These results led to reduced prescription patterns due to a high risk of cardiovascular diseases as well as an increased risk for breast cancer if HRT had been administered. Both ongoing analyses of subgroups and other studies extenuated the WHI data, since the increased risks were neither generalizable to the typical postmenopausal patient (regarding age and risk profile) nor to the medication being used today. This article summarizes all aspects of HRT in peri- and postmenopausal women (indications, contraindications, practical approaches, risks, prevention) and provides recommendations with respect to the most recent S3 guideline.

Vaginal prevalence of human papillomavirus infections in women with uterovaginal aplasia before and after laparoscopically assisted creation of a neovagina: a prospective epidemiological observational study.

OBJECTIVE: To study vaginal as opposed to cervical human papillomavirus (HPV) acquisition with regard to true prevalence, HPV types, and the role of co-factors in virgins and after their sexual debut. DESIGN: Prospective epidemiological observational study. SETTING: University hospital specialised in genital malformations. POPULATION: Women diagnosed with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) and undergoing neovaginoplasty between November 2011 and July 2017. METHODS: This is a prospective study including 186 women with MRKHS before and after sexual debut. MAIN OUTCOME MEASURES: Conventional vaginal cytology and different HPV tests were performed at surgery and during routine gynaecological follow-up 1, 3, 6 and ≥ 11 months after surgery and risk factors were documented. RESULTS: The mean age of all women at surgery was 20.1 years (SD 5.4), mean body mass index (BMI) was 22.1 kg/m2 (SD 4.6). In 83 vaginal samples from 41 different women at least one of the HPV tests was positive. Thirty-three different HPV types were detected. The prevalence of 41/186 = 22.0% as well as type distribution are comparable with those found in a young German female population. The overall rate of acquisition was clearly associated with sexual activity and smoking habits. Out of 367 Papanicolaou smears only six were abnormal with Pap IIID (MN II) and no obvious vaginal lesion was detected. CONCLUSIONS: Vaginal HPV prevalence and HPV types in previously virgin women after creation of a neovagina are not different from the acquisition of cervical infections in the general population and is clearly associated with sexual activity and with smoking habits. However, abnormal Papanicolaou smears are rarely seen. TWEETABLE ABSTRACT: Vaginal HPV prevalence after creation of a neovagina is similar to that on the cervix in the general population.

Practical recommendations for fertility preservation in women by the FertiPROTEKT network. Part I: Indications for fertility preservation.

PURPOSE: Most guidelines about fertility preservation are predominantly focused on scientific evidence, but are less practically orientated. Therefore, practically oriented recommendations are needed to support the clinician in daily practice. METHODS: A selective literature search was performed based on the clinical and scientific experience of the authors, focussing on the most relevant diseases and gynaecological cancers. This article (Part I) provides information on topics that are essential for the fertility preservation indication, such as disease prognosis, disease therapy and its associated risks to fertility, recommending disease-specific fertility preservation measures. Part II specifically focusses on fertility preservation techniques. RESULTS: In breast cancer patients, fertility preservation such as ovarian tissue and oocyte cryopreservation is especially recommended in low-stage cancer and in women < 35 years of age. In Hodgkin's lymphoma, the indication is mainly based on the chemotherapy regime as some therapies have very low, others very high gonadotoxicity. In borderline ovarian tumours, preservation of fertility usually is achieved through fertility sparing surgery, ovarian stimulation may also be considered. In cervical cancer, endometrial cancer, rheumatic diseases and other malignancies such as Ewing sarcoma, colorectal carcinoma, non-Hodgkin lymphoma, leukaemia etc., several other factors must be considered to enable an individual, stage-dependent decision. CONCLUSION: The decision for or against fertility preservation depends on the prognosis, the risks to fertility and individual factors such as prospective family planning.

Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates.

STUDY QUESTION: What is the success rate in terms of ovarian activity (menstrual cycles) as well as pregnancy and delivery rates 1 year after orthotopic ovarian transplantations conducted in a three-country network? SUMMARY ANSWER: In 49 women with a follow-up >1 year after transplantation, the ovaries were active in 67% of cases and the pregnancy and delivery rates were 33 and 25%, respectively. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. However, published case series have not allowed either a more detailed analysis of patients with premature ovarian insufficiency (POI) or calculation of success rates based on the parameter 'tissue activity'. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of 95 orthotopic transplantations in 74 patients who had been treated for cancer, performed in the FertiPROTEKT network from 2008 to June 2015. Of those 95 transplantations, a first subgroup (Subgroup 1) was defined for further analysis, including 49 women with a follow-up period >1 year after transplantation. Of those 49 women, a second subgroup (Subgroup 5) was further analysed, including 40 women who were transplanted for the first time and who were diagnosed with POI before transplantation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Transplantation was performed in 16 centres and data were transferred to the FertiPROTEKT registry. The transplantations were carried out after oncological treatment had been completed and after a remission period of at least 2 years. Tissue was transplanted orthotopically, either into or onto the residual ovaries or into a pelvic peritoneal pocket. The success rates were defined as tissue activity (menstrual cycles) after 1 year (primary outcome) and as pregnancies and deliveries achieved. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of all transplanted 74 women was 31 ± 5.9 years at the time of cryopreservation and 35 ± 5.2 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded. In Subgroup 1, tissue was cryopreserved at the age of 30 ± 5.6 and transplanted at 34 ± 4.9 years. Ovaries remained active 1 year after transplantation in 67% of cases (n = 33/49), the pregnancy rate was 33% (n = 16/49) and the delivery rate was 25% (n = 12/49). In Subgroup 5, tissue was cryopreserved at the age 30 ± 5.9 years and transplanted at 34 ± 5.2 years. Ovaries remained active 1 year after transplantation in 63% of cases (n = 25/40), the pregnancy rate was 28% (n = 11/40) and the delivery rate was 23% (n = 9/40). The success rates were age dependant with higher success in women who cryopreserved at a younger age. In Subgroup 5, tissue was exclusively transplanted into the ovary in 10% (n = 4/40) of women and into a peritoneal pocket in 75% (n = 30/40), resulting in spontaneous conceptions in 91% of patients (n = 10/11). LIMITATIONS, REASONS FOR CAUTION: The data were drawn from a retrospective analysis. The cryopreservation and transplantation techniques used have changed during the study period. The tissue was stored in many tissue banks and many surgeons were involved, leading to heterogeneity of the procedures. However, this does reflect the realistic situation in many countries. Although patients with POI were evaluated before transplantation to allow specific analysis of the transplanted tissue itself, the possibility cannot be excluded that residual ovarian tissue was also reactivated. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest case series worldwide to date and it confirms that cryopreservation and transplantation of ovarian tissue can be a successful option for preserving fertility. Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomized study is required. STUDY FUNDING/COMPETING INTEREST: This study was in part funded from the Deutsche Forschungsgemeinschaft (# DI 1525) and the Wilhelm Sander Foundation (2012.127.1) and did not receive any funding from a commercial company. No competing interests. TRIAL REGISTRATION NUMBER: None.

Fertility preservation methods in young women with systemic lupus erythematosus prior to cytotoxic therapy: experiences from the FertiPROTEKT network.

OBJECTIVES: Despite new treatment options, some patients with systemic lupus erythematosus (SLE) need to be treated with the cytotoxic agent cyclophosphamide (CYC). Unlike malignant disease, there are no recommendations for ovarian protection in SLE. The clinical experience of the FertiPROTEKT network as well as recommendations after literature review will be presented in this paper. METHODS: Retrospective analyses of counselling and treatment data from the FertiPROTEKT register with special respect to SLE patients under 40 years prior to planned CYC treatment. RESULTS: A total of 2836 patients were advised prior to cytotoxic treatment in one of the FertiPROTEKT centres during January 2007 to November 2011. Of those, 68 patients (mean age 25 +/- 6.07 years) were counselled for severe SLE. Only five women did not make use of a fertility preservation method. Sixty-three patients (92.6%) decided in favour of a fertility preservation method. The largest proportion (91.2%) opted for treatment with a GnRH analogue. Ovarian tissue removal for cryoconservation was performed in 16 patients (25%). Stimulation therapy for cryoconservation of fertilized egg cells was performed in three patients (4.4%). CONCLUSIONS: When counselling patients with SLE for fertility preservation one has to be aware of the disease-specific risks. According to the literature, a safe and effective option in SLE up to now has been the use of a GnRH analogue. Cryoconservation of ovarian tissue must still be seen as an experimental treatment, but as data on removal, cryoconservation, retransplantation and pregnancies are steadily rising, this presents a promising option for young SLE patients. Cryoconservation of oocytes must be very critically evaluated due to the need for a stimulation therapy and should only be performed after particular consideration of the individual risks.

Impact of systemic lupus erythematosus on ovarian reserve in premenopausal women: evaluation by using anti-Muellerian hormone.

Systemic lupus erythematosus (SLE) is an autoimmune disease which may negatively influence fertility. Treatment with cyclophosphamide can damage the ovaries. The ovarian function can also be reduced by autoimmune oophoritis in lupus patients. We analysed the influence of SLE on the ovarian reserve against disease intensity and duration of illness. We determined the ovarian reserve in 33 premenopausal SLE patients without previous cyclophosphamide-treatment by measuring the anti-Muellerian hormone (AMH) and compared these with the AMH values of 33 age-matched healthy controls. Numbers of children and miscarriages were reported. Disease intensity of the SLE patients was determined using SLEDAI and ECLAM and duration of illness was taken into account. We found that the AMH values in the SLE group were significantly lower than in the healthy control group. No significant differences between the groups regarding number of children and miscarriages were noted and no correlation between the AMH value and the duration of illness or the SLEDAI as an indicator of disease activity was found. Despite mild disease activity SLE patients had a significantly lower ovarian reserve than age-matched healthy women. This could be a sign that SLE itself has a negative influence on the ovarian reserve.

Fertility preservation in girls and adolescents before chemotherapy and radiation - review of the literature.

There has been a significant improvement in survival rates over the last decade as a result of advances in the treatment of cancer in children. One of the consequences of chemotherapy may be damage to the ovarian function, which can lead to loss of fertility. Methods of fertility protection have been developed for adult women as a result of advances in reproductive medicine, which make the option of becoming pregnant after surviving cancer realistic. However, only some of the methods can be used in prepubescent girls and adolescents. In addition, a higher number of miscarriages and premature births have been found in women who underwent pelvic radiotherapy during childhood or adolescence and the children were more commonly growth retarded. The effects of cancer treatment on the ovarian function and later fertility should be discussed at the start of treatment.

[Fertility preservation for young patients with autoimmune diseases and the need for cytotoxic treatment. Clinical experiences from interdisciplinary consultation]. / Fertilitätserhaltende Maßnahmen bei jungen Frauen mit Autoimmunerkrankung vor zytotoxischer Therapie : Erfahrungen aus einer interdisziplinären Sprechstunde.

In cases of severe exacerbation of autoimmune diseases (AID) cytotoxic therapy, in particular with cyclophosphamide (CYC) is needed. As the peak occurrence of such AIDs occurs in young women during the childbearing years, preservation of fertility and the hormonal function of the ovaries are an interdisciplinary challenge.For ovarian protection several options exist. Gonadotropin-releasing hormone analogues in parallel with CYC treatment seem to reduce the cytotoxic effect on the ovaries. Fertilized and unfertilized oocytes can be conserved by cryoconservation after ovarian stimulation. A relatively new strategy uses cryopreservation and autotransplantation of human ovarian tissue prior to cytotoxic therapy. As all these methods are accompanied with side-effects and possible delays in the necessary CYC treatment, a close collaboration of gynecologists and internists is needed. The decision for the optimal preservation therapy should always be based on the individual patient.

Management of fertility preservation in young breast cancer patients in a large breast cancer centre.

PURPOSE: The increase of breast cancer in young women under 40 years and the increasing age of women at the time of the birth of their first child underlines the importance to implement counselling for fertility-preserving strategies in the management of breast cancer care. We present the fertility-preserving procedures performed after routine counselling for primary breast cancer patients in a large certified breast cancer centre. MATERIALS AND METHODS: Since November 2006, patients aged below 40 years with histologically confirmed breast cancer are routinely counselled on fertility-preserving possibilities before breast surgery and chemotherapy in the fertility centre of the University Women's Hospital in Tuebingen. The recommendations are based on the treatment recommendations of the network FertiPROTEKT. RESULTS: During the last 40 months, 56 primary breast cancer patients were counselled. Forty-one of these patients were hormone receptor positive. Thirty-four patients (63%) underwent fertility-preserving strategies. The majority of the patients (n = 22) decided on ovarian tissue cryopreservation. GnRH protection was performed in 14 patients. In 12 patients an ovarian stimulation protocol was initiated to cryopreserve fertilized or unfertilized oocytes. A combination of different fertility-preserving methods was performed in 12 patients. CONCLUSIONS: The preservation of ovarian function and fertility are of great importance to young breast cancer patients. Counselling on fertility-preserving strategies is therefore critical in these patients and should be routinely performed.

Fertility preservation in prepubertal girls prior to chemotherapy and radiotherapy--review of the literature.

Significant improvement in the survival rates of children with pediatric cancers has been achieved over the last 25 years, so the number of long-term survivors is increasing and their subsequent quality of life is of increasing importance. One of the most serious side effects of chemotherapy or radiotherapy is damage to the ovarian function, which can lead to loss of fertility. The degree of this damage depends on the substances used, the dose of radiotherapy reaching the ovaries, and the age of the girl at the time of treatment. Up to now, the only established method of fertility preservation has been cryoconservation of fertilized egg cells or embryos, but this is not possible in prepubertal girls because of their sexual immaturity. Removal of ovarian tissue and subsequent cryoconservation with the option of later orthotopic retransplantation is therefore an option to these girls. This method can lead to pregnancy and birth in adult women. Up to now there are no studies about the retransplantation of ovarian tissue which was removed before puberty. Displacement of the ovaries away from the radiation field before radiation to the pelvic area can be considered; however, the data is controversial. One problem in the use of fertility preservation methods in these very young patients is that they undergo procedures which, because of their age, they mostly do not understand and the parents must make a decision based on the assumed later wishes of their daughter.

Postmenopausal bleeding as first sign of an acute myelogenous leukaemia: A case report and review of the literature.

Postmenopausal bleeding (PMB) can have various causes and malignancy must always be excluded. Extramedullary manifestations of a haematological disease in the female genital tract are rare. We present the case of a woman with PMB as the first sign of an acute myelogenous leukaemia (AML). An 81-year-old patient presented with PMB. Manual and colposcopic examination raised suspicion of a cervical carcinoma, but histopathology and cervical Pap smear altered the diagnosis to granulocytic sarcoma (GS), an extramedullary manifestation of AML. The patient had a normal blood count 2 weeks prior to the examination, but at the time of presentation her leukocytes had risen to 116000/microl. The patient died 3 days later due to a pulmonary embolism, most probably as a result of leukostasis. In this case, GS of the cervix was the first sign of the AML with simultaneous appearance of leukocytosis and peripheral blasts. PMB was the reason for presentation. GS of the female genital tract is very rare and diagnosis is challenging, especially on the basis of the Pap smear. Abnormal inflammatory cells must be a warning sign and an indication for further examinations. GS as the presenting sign of AML has a poor prognosis with only 6% of patients surviving for more than 2 years.