Evaluation of oncofertility care in childhood cancer patients: the EU-Horizon 2020 twinning project TREL initiative.

Background: The 5-year survival rate of childhood cancer exceeds 80%, however, many survivors develop late effects including infertility. The aim of this study was to evaluate the current status of oncofertility care at Vilnius University Hospital Santaros Klinikos (VULSK) within the framework of the EU-Horizon 2020 TREL project. Methods: All parents or patients aged 12-17.9 years treated from July 1, 2021 until July 1, 2022 were invited to complete an oncofertility-care-evaluation questionnaire. After completing the questionnaire, patients were triaged to low-risk (LR) or high-risk (HR) of gonadal damage using a risk stratification tool (triage). Data was assessed using descriptive statistics. Results: Questionnaires were completed by 48 parents and 13 children triaged as 36 (59%) LR and 25 (41%) HR patients. Most HR respondents (21/25, 84%) were not counseled by a fertility specialist. Six boys (4 HR, 2 LR) were counseled, none of the girls was counseled. Three HR boys underwent sperm cryopreservation. Only 17 (27.9%, 9 HR, 8 LR) respondents correctly estimated their risk. All counseled boys (n = 6) agreed the risk for fertility impairment had been mentioned as compared to 49.1% (n = 27) of uncounseled. All counseled respondents agreed they knew enough about fertility (vs. 42%). Conclusions: Respondents counseled by a fertility specialist were provided more information on fertility than uncounseled. HR patients were not sufficiently counseled by a fertility specialist. Based on the current experience oncofertility care at VULSK will be improved.

Challenges in the Diagnosis of XY Differences of Sexual Development.

Background: We report the clinical case of female patient with 46,XY difference of sexual development (DSD) and discuss the challenges in the differential diagnosis between complete gonadal dysgenesis (also called Swyer syndrome) and complete androgen insensitivity syndrome. Case Presentation: The patient's with primary amenorrhea gynaecological examination and magnetic resonance imaging (MRI) revealed the absence of the uterus and a very short vagina. Two sclerotic structures, similar to ovaries, were recognised bilaterally in the iliac regions. Hormonal assay tests revealed hypergonadotropic hypogonadism and the testosterone level was above normal. The karyotype was 46,XY and a diagnosis of Swyer syndrome was made. At the age of 41, the patient underwent a gynaecological review and after evaluating her tests and medical history, the previous diagnosis was questioned. Therefore, a molecular analysis of sex-determining region Y (SRY) and androgen receptor (AR) genes was made and the results instead led to a definite diagnosis of complete androgen insensitivity syndrome. Conclusions: The presented case illustrates that differentiating between complete gonadal dysgenesis and complete androgen insensitivity can be challenging. A well-established diagnosis is crucial because the risk of malignancy is different in those two syndromes, as well as the timing and importance of gonadectomy.

Development of a questionnaire to evaluate female fertility care in pediatric oncology, a TREL initiative.

BACKGROUND: Currently the five-year survival of childhood cancer is up to 80% due to improved treatment modalities. However, the majority of childhood cancer survivors develop late effects including infertility. Survivors describe infertility as an important and life-altering late effect. Fertility preservation options are becoming available to pre- and postpubertal patients diagnosed with childhood cancer and fertility care is now an important aspect in cancer treatment. The use of fertility preservation options depends on the quality of counseling on this important and delicate issue. The aim of this manuscript is to present a questionnaire to determine the impact of fertility counseling in patients suffering from childhood cancer, to improve fertility care and evaluate what patients and their parents or guardians consider good fertility care. METHODS: Within the framework of the EU-Horizon 2020 TREL project, a fertility care evaluation questionnaire used in the Netherlands was made applicable for international multi-center use. The questionnaire to be used at least also in Lithuania, incorporates patients' views on fertility care to further improve the quality of fertility care and counseling. Results evaluate fertility care and will be used to improve current fertility care in a national specialized pediatric oncology center in the Netherlands and a pediatric oncology center in Lithuania. CONCLUSION: An oncofertility-care-evaluation questionnaire has been developed for pediatric oncology patients and their families specifically. Results of this questionnaire may contribute to enhancement of fertility care in pediatric oncology in wider settings and thus improve quality of life of childhood cancer patients and survivors.

A crosscut survey on reproductive health in Lithuanian childhood cancer survivors.

OBJECTIVES: Sexual dysfunction was reported to compromise the quality of life in childhood cancer survivors. The aim of our study was to evaluate the reproductive health in long-term pediatric cancer survivors by conducting a crosscut survey. MATERIAL AND METHODS: Childhood cancer survivors over 18 years of age, who were in remission for more than 5 years, were invited to complete a gender-specific questionnaire surveying on their reproductive health. Demographic and treatment data were retrieved from their medical records. Treatment modalities were reviewed for its potential gonadotoxicity. RESULTS: 34 (17 males and 17 females, respectively) from 346 addressed survivors (9.8%) completed the questionnaire. Median age and follow-up after diagnosis was 27 (18-35) and 14 (3-25) years, respectively. Some respondents reported sexual concerns: 11.8% males experienced problems with penetration, two males (11.8%) who underwent semen analysis were found to be azoospermic. Similarly, 11.8% females reported delayed puberty, the average age of menarche was 14 (12-17) years, 29.4% females reported irregular menstrual cycles. Cyclophosphamide equivalent dose (CED) differed significantly between the patients treated for leukemia, lymphoma and solid tumors (3000 vs 4352 vs 6660 mg/m2, respectively, p = 0.014). CONCLUSIONS: Low prevalence of sexual dysfunction, fertility related disorders or delayed puberty in childhood cancer survivors was found. However, the results should be interpreted with caution taking into account a low response rate.

The use of vaginal wet smear: can we predict Mycoplasmas/Ureaplasmas?

PURPOSE: To evaluate the agreement of wet smear microscopy with Gram stain microscopy and to assess whether it is possible to predict Mycoplasmas/Ureaplasmas when analysing vaginal secretion with Gram stain and wet smear microscopy. METHODS: Women with complaints of the abnormal vaginal discharge were invited to participate. A sample of vaginal secretion was taken for wet smear microscopy and for Gram staining analysis. A sample from the endocervical canal was taken for DNA detection of seven infections: Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma parvum, Ureaplasma urealyticum, Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis. The percentage agreement between wet smear and Gram stain was determined and the Cohen's Kappa values were calculated. RESULTS: Of 158 consecutive women included, one (or a few) of the infections were detected in 54% of them and the most frequent infection was Ureaplasma parvum (79% of all the cases with infections). The percentage agreement between vaginal wet smear and Gram stain was 73% (Cohen's Kappa value 0.63). A statistically significant association between the DNA detected Mycoplasmas/Ureaplasmas and bacterial vaginosis was found (positive amine test p = 0.046, wet smear p = 0.005 and Gram stain p = 0.03). CONCLUSIONS: There was a statistically significant association between bacterial vaginosis and the DNA detected Mycoplasmas/Ureaplasmas. The agreement of vaginal wet smear with Gram stain was good.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Squamous Vaginal Papillomatosis in Prepubertal Female Twins: A Case Report.

This is the first case describing vaginal papillomatosis with a fibroepithelial polyp of the vulva in a prepubertal girl and vaginal papillomatosis in her twin sister. Parents contacted pediatric urologist regarding their eight-year-old daughter (twin A), who had a growth next to the external urethral meatus. The girl was referred to a pediatric surgeon. The exophytic 3 cm long structure with necrosis on top was found. After obtaining informed consent from girl parents, pediatric surgeon removed the exophytic structure and perform cystoscopy and vaginoscopy for possible changes in the bladder and vagina. Cystoscopy findings were normal. On vaginoscopy, numerous macroscopic papillomatous structures were identified on the cervix and vaginal walls. Vaginal biopsies were performed on the areas affected by papillomatosis. Histopathologic examination showed a fibroepithelial polyp with a central fibrovascular core covered by squamous epithelium and vaginal squamous papillomatosis. The decision was made to perform vaginoscopy on her twin sister (twin B), too. On vaginoscopy, solitary small vaginal papillomas were also found. In this case manifestation of vaginal papillomatosis in twins might have been influenced by inheritance and the same bacterial and viral environment.

Dysgerminoma in a Prepubertal Girl with Complete 46XY Gonadal Dysgenesis: Case Report and Review of the Literature.

BACKGROUND: Complete 46XY gonadal dysgenesis (Swyer syndrome) is a rare and challenging diagnosis among prepubertal girls, as estrogen insufficiency becomes evident only during adolescence, with nonspecific symptoms such as primary amenorrhea and/or delayed puberty. Unfortunately, girls with Swyer syndrome are at high risk for malignancies in the dysgenetic gonads, which can be prevented only by performing prophylactic bilateral gonadectomy. CASE: We present a 9-year-old patient with Swyer syndrome diagnosed with dysgerminoma in the right gonad and gonadoblastoma in the left gonad after prophylactic bilateral gonadectomy. SUMMARY AND CONCLUSION: Concerning the high risk of early gonadoblastoma and its malignant transformation, we recommend performing prophylactic bilateral gonadectomy at the time of diagnosis, even if the patient is prepubertal.

Endometrial biopsy and density of nerve fibers in eutopic endometrium. Looking for easier ways to diagnose endometriosis.

The purpose of study was to evaluate if there is any difference between nerve fibers density in eutopic endometrium in women with and without endometriosis. The prospective case - control study conducted between October 2013 and December 2015. The study included 60 reproductive age women undergoing laparoscopy for suspected endometriosis, pelvic pain, or infertility and not currently receiving hormonal treatment for at least 3 months prior to laparoscopy. Immunohistochemical nerve fiber detection in endometrial curetting using anti-gene product 9.5 was compared with surgical diagnosis. The nerve fibers were detected in eutopic endometrium in women with and without endometriosis. PGP9.5 positive nerve fibers were found in 26 (43%) cases: 16 (50%) in women with endometriosis and 10 (36%) in women without endometriosis. The mean nerve fiber density was higher in the group with endometriosis (0.53 per mm2 ± 0.68) than without endometriosis (0.48 per mm2 ± 0.89), but no statistically significant difference was observed (p > .05). Test specificity was 64.3%, sensitivity 50%, positive predictive value - 61.5%, negative predictive value - 52.9%, and overall accuracy 56.7%. The detection of PGP9.5 positive nerve fibers in eutopic endometrium cannot be used as a reliable diagnostic test of diagnosing endometriosis.

The risk factors of dysmenorrhea in young women.

OBJECTIVE: The Aim: To evaluate risk factors for dysmenorrhea in women of reproductive age and to review its characteristics. PATIENTS AND METHODS: Material and Methods: A questionnaire was conducted among 354 women followed by a statistical analysis of the gathered data. RESULTS: Results: Among the interviewed women 84.2 % suffer from painful menstruations. Women under 25 years of age are more likely to experience pain, which reduces with age. Dysmenorrhea is more common among women whose menstrual cycles are irregular (92.5%) with a number of bleeding days 4-7 (90.7 %), though still occurring within the normal 21-35 days interval (87.6 %). Nulliparous women are more likely to experience menstrual pain (89.9 %). CONCLUSION: Conclusion: Dysmenorrhea depends on women's age, length of menstrual bleeding, length of menstrual cycle and its regularity, age at menarche and parity, but does not depend on body mass index and smoking status.

Reproductive health of female childhood cancer survivors.

Current treatment schemes of childhood cancer are usually effective enough to enable successful management of the disease. With the high rates of survival, another problem arises because patients often suffer much later from side effects of the toxic therapy. A common complication caused by cancer treatment is impairment of the female reproductive system including dysfunction of the hypothalamus and hypophysis, the killing of gonadal cells, and uterine injury. This may lead to altered pubertal timing, gonadotropin insufficiency or deficiency, acute ovarian failure, premature ovarian insufficiency, sexual dysfunction, and complicated pregnancy. The severity of these side effects depends a lot on the patient's age at treatment and the particularities of their chemo- and/or radiotherapy regimens. While some types of cancer require aggressive treatment, and therefore negative side effects cannot be avoided, strategies which preserve the patient's reproductive potential are essential. Such strategies are more established in the treatment of adult women, however there are also promising opportunities in the treatment of pediatric oncology patients. Ovar-ian transposition is already widely applied before pelvic radiotherapy. Cryopreservation of ovarian tissue, cryopreservation and in vitro maturation of immature oocytes, or cryopreservation of mature oocytes when the patient's age is appropriate, have also shown to have promising results in pediatric patients. Concurrent combinations of several techniques can also be successful. Counselling of pediatric patients and their families is challenging, and the urgent commencement of anticancer therapies often discourages attempts to preserve the girl's reproductive system. Given that successful methods of fertility preserva-tion are already accessible, it is crucial not to leave this topic aside at the time of diagnosis.

Rationale and design of ASTEROID 2, a randomized, placebo- and active comparator-controlled study to assess the efficacy and safety of vilaprisan in patients with uterine fibroids.

BACKGROUND: Uterine fibroids (UFs) may be treated with progesterone receptor modulators (PRMs), which have been shown to reduce heavy menstrual bleeding and the size of UFs. To date, one PRM (ulipristal acetate) has received regulatory approval for the treatment of UFs; therapy comprises intermittent treatment courses of up to 3months each, followed by a break to allow two menstruations to occur. We report the design of ASTEROID (Assess Safety and efficacy of vilaprisan in patients with uTERine fibrOIDs) 2, a phase 2 study examining the efficacy and safety of a novel PRM, vilaprisan, in women with UFs. METHODS/DESIGN: In this randomized multi-arm study, vilaprisan (2mg daily) will be administered in different regimens: continuous treatment for 12 or 24weeks, or two 12-week treatment periods separated by a break to allow one menstruation to occur. Efficacy and safety will be compared with that of ulipristal acetate (5mg daily) and placebo. Patients randomized to receive placebo for 12weeks will also be given active treatment for 12weeks. The primary measure of efficacy will be amenorrhoea rate; secondary measures include time to normalized menstrual bleeding and percentage change in UF volume. Endometrial changes will be monitored throughout the study. DISCUSSION: The placebo- and active comparator-controlled trial ASTEROID 2 is the first study to evaluate systematically the efficacy and safety of different treatment regimens of PRMs in women with UFs. The findings of this study will direct the planning of future clinical trials of vilaprisan.

The effect of a drospirenone-containing combined oral contraceptive on female sexual function: a prospective randomised study.

OBJECTIVES: The study investigated the effects on female sexual function of a progestogen-containing combined oral contraceptives (COCs) with an antiandrogenic profile taken in a continuous regimen. METHODS: In this prospective randomised single-institution study, 80 healthy women with a monogamous partner and an active sexual life were randomised into two groups for a period of 3 months. Women in the exposed group (n = 40) took a COCs containing 30 µg ethinylestradiol (EE) and 3 mg drospirenone (DRSP) in a 21/7 regimen. Women in the control group (n = 40) used either a barrier contraceptive method (BCM) or a natural family planning method (NFPM). Participants were asked to complete a set of validated questionnaires to assess sociodemographic variables and measure Female Sexual Function Index (FSFI). RESULTS: The total FSFI score (p < 0.0001), as well as the desire (p = 0.04) and arousal (p = 0.03) scores, were significantly lower in the COCs group after 3 months of hormonal contraceptive use compared with baseline. Women using BCM or NFPM showed an improvement in total FSFI score (p = 0.02). Hormonal contraception with DRSP increased the likelihood of worse sexual function in the desire (odds ratio [OR] 2.47; 95% confidence interval [CI] 1.22, 4.98; p = 0.01) and arousal domains (OR 2.85; 95%CI 1.34, 5.93; p = 0.005) and in total FSFI score (OR 2.01; 95%CI 1.45, 2.79; p < 0.001). The results remained statistically significant even after adjustment for smoking status. CONCLUSIONS: The study found evidence that women taking a combined EE/DRSP COCs for 3 months may have a worsening of sexual function as measured by FSFI.

Uterine size and ovarian size in adolescents with functional hypothalamic amenorrhoea.

INTRODUCTION: Functional hypothalamic amenorrhoea (FHA) is a condition characterised by the absence of menses due to suppression of the hypothalamic-pituitary-ovarian axis. OBJECTIVE: The purpose of the study was to estimate uterine and ovarian sizes in adolescents with FHA and to compare these results with findings in peers having regular menstrual cycles. DESIGN: Prospective case-controlled study. SETTINGS: Vilnius University Hospital Santariskiu Klinikos, Lithuania. PATIENTS: Lithuanian adolescents--45 with FHA and 40 comparison group participants. MAIN OUTCOME MEASURES: We assessed ultrasound measurements of internal reproductive organs, levels of luteinising hormone, follicle-stimulating hormone, prolactin, oestradiol and calculated body mass index (BMI). RESULTS: The mean age of the participants was 16.3 ± 1.2 years, the mean age after menarche--3.6 years. In adolescents with FHA the BMI was 17.8 ± 1.8 kg/m(2) and 20.4 ± 1.4 kg/m(2) in the comparison group, p < 0.001. The uterine volume (14.7 ± 6.3 cm(3) vs 31.7 ± 10.6 cm(3), p < 0.001), cervical length (2.3 ± 0.4 cm vs 2.6 ± 0.5 cm, p = 0.03), volume of both ovaries (9.3 ± 3.6 cm(3) vs 13.8 ± 4.3 cm(3), p < 0.001) and levels of LH (2.70 ± 2.59 vs 6.01 ± 2.44, p < 0.001) were significantly lower in girls with FHA. A significantly positive correlation between volume of uterus and levels of LH (r = 0.415; p < 0.001) was found. We identified a positive correlation between uterine volume, uterine corpus length, cervical length, ovarian volume and weight, BMI. CONCLUSIONS: In adolescents with FHA the dimensions of uterus and ovaries were smaller than in girls having regular menstrual cycles. Our study confirmed the influence of oestrogen on uterus size: oestrogen deficiency causes a reduction in uterine size. Uterine size and ovarian size correlate positively with BMI.

Sexual behavior and high-risk human papillomavirus in 15- to 22-year-old Lithuanian women.

We determined the risk of high-risk human papillomavirus (HR-HPV) infection in 169 15- to 22-year-old sexually active Lithuanian women attending two outpatient clinics in Vilnius. The Digene(®) Hybrid Capture II DNA test was used to test for HR-HPV infection on material collected by cervical swabs. The findings were compared with the pattern of sexual behavior as given in questionnaire replies. The overall risk of HR-HPV was 23.1%, but 60.0% in adolescents ≤15 years old. Mean age at first intercourse was 17.1 years; 73.5% of women had only had one sexual partner and 24.5% more than one. The risk of HR-HPV was higher in women with more than one sexual partner, and related to being a smoker and to early age at the first intercourse. Our results confirm that smoking, early coitarche, multiple sexual partners and unprotected vaginal intercourse are related to the risk of HR-HPV infection in young women.

[Evaluation and treatment of adolescent girls with hirsutism]. / Diagnostyka i leczenie hirsutyzmu u dziewczat.

Clinical manifestations of androgen excess which are skin and hair related (hirsutism, acne, alopecia) are common and distressing symptoms for an adolescent girls. During puberty and at the time of the first menstruation cycles, physiological hyperandrogenism can be observed. The causes of hirsutism can be various, including familial, idiopathic, and those, caused by excess androgen secretion by the ovary (PCOS, tumors), or by adrenal glands (congenital adrenal hyperplasia, tumor), or exogenous pharmacologic sources of androgens. The diagnosis and treatment of hirsutism remains quite problematic due to innumerous endocrinologic aspects and unsatisfactory treatment results. Androgen excess during puberty must be appropriately recognized, clinically evaluated and treated. Pharmacologic and cosmetic treatments may have beneficial effect. Oral contraceptives and antiadrogens combinations may be recommended as the treatment of choice in adolescents.

[Casual analysis of menstrual disorders in adolescent girls]. / Analiza przyczyn zaburzen miesiaczkowania u mlodocianych.

OBJECTIVES: Menstrual disorders are very common during the early postmenarcheal years. This study was undertaken to determine the causes of menstrual disorders in adolescents. MATERIALS AND METHODS: In the research there were included 117 girls 14-18 years old without evidence of androgen excess (hirsutism, acne): the study group consisted of 87 adolescents with menstrual disorders and the control group of 30 girls with regular menstrual cycles. All the patients underwent gynecological and ultrasound examination and an analysis of the hormonal status. RESULTS: The data from our investigation show that 43.7% of adolescents with menstrual dysfunction have eating disorders, 16.1%--immaturity of hypothalamic-pituitary-ovarian axis, 13.8%--polycystic ovary syndrome, 9.2%--hyperprolactinemia, 4.6%--delayed puberty, 3.4%--genetic defect and 9.2% other reasons. CONCLUSIONS: A thorough history and physical examination focusing on the basic understanding of pubertal and menstrual physiology and pathology allows to obtain an accurate diagnosis. The prognosis for later fertility depends on the preventive measures token in adolescence.