Anti-Müllerian hormone for screening, diagnosis, evaluation, and prediction: A systematic review and expert opinions.

AIM: To present evidence-based recommendations for anti-Müllerian hormone (AMH) measurement as an ovarian reserve test. METHODS: A systematic literature search for the clinical utility of AMH was conducted in PubMed from its inception to August 2022 to identify studies, including meta-analyses, reviews, randomized controlled trials, and clinical trials, followed by an additional systematic search using keywords. Based on this evidence, an expert panel developed clinical questions (CQs). RESULTS: A total of 1895 studies were identified and 95 articles were included to establish expert opinions subdivided into general population, infertility treatment, primary ovarian insufficiency, polycystic ovary syndrome, surgery, and oncofertility. We developed 13 CQs and 1 future research question with levels of evidence and recommendations. CONCLUSION: The findings of the current systematic review covered the clinical utility of AMH including its screening, diagnosis, evaluation, and prediction. Although some clinical implications of AMH remain debatable, these expert opinions may help promote a better understanding of AMH and establish its clinical significance.

AMH producing purely cystic virilizing adult granulosa cell tumor in 17 years old girl: a case report and review of literatures.

BACKGROUND: Androgen-producing granulosa cell tumor in adolescent girl is rare condition and clinical characteristics are not fully elucidated. CASE PRESENTATION: Seventeen years old girl complained of secondary amenorrhea was referred to our out-patient consultation. Markedly elevated serum testosterone, LH, and AMH levels were noted. Mild hirsutism and clitoromegaly were presented. Transabdominal ultrasonography and MRI revealed cystic mass occupied pelvic cavity probably originated from left ovary. Right ovary showed polycystic appearance. Laparoscopic left ovarian cystectomy was performed. After the surgery, her menstruation resumed along with normalized hormonal parameters, and clinical hyperandrogenism were improved. Since the scarcity of cellular lining of inner cyst wall, definitive pathological diagnosis was difficult. After the consultation with gynecological pathologist, the tumor was diagnosed as sex cord stromal tumor, highly suspicious for adult granulosa cell tumor. Residual left salpingo-oophorectomy was performed by additional laparoscopic surgery. Her serum testosterone and AMH levels were remained low with regular menstrual cycles and no evidence of recurrence. CONCLUSIONS: Androgen-producing cystic granulosa cell tumor is rare gynecological disorders, which need both gynecologic oncological and endocrinological approach. Its clinical manifestations may bring some clues to the pathogenesis of ovulatory dysfunctions, such as polycystic ovary syndrome.

Accumulation of fibrosis and altered perifollicular stromal differentiation in vitrified-thawed human ovarian tissue xenografted to nude mice.

Purpose: Ovarian tissue cryopreservation and its auto-transplantation is promising technique in fertility preservation. Longevity of grafted tissue is limited though mechanism of follicle reduction is not fully understood. We evaluated histological alteration of vitrified-thawed ovarian tissue that grafted to nude mice. Materials and Methods: Human ovarian tissue was cryopreserved by vitrification. After thawing, they were grafted to mesentery of nude mice. Twelve weeks after transplantation, the implants were removed and histologically examined. The presence of follicles, the degree of fibrosis, and TUNEL staining in surrounding cortex were evaluated. The stromal expressions of alpha-smooth muscle actin (aSMA) were determined. Results: Normal ovarian cortex was decreased, and fibrotic area were significantly increased after grafting. The distributions of developmental stage of follicles shifted toward activation of follicular growth. Stromal TUNEL staining was increased in frozen/thawed tissue. The expression of aSMA were found in perifollicular stroma of growing follicles, which were decreased in grafted tissue associated with reduction of cortical stroma. Conclusions: Fibrosis, reduced cortical stroma, and activation of dormant follicles were concomitantly observed in grafted ovarian cortex, which may relate to limited longevity. Perifollicular aSMA expression can be regarded as a marker of the competence of cortical stroma that regulate follicular development.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

Decreased occurrence of endometriosis in women with Chlamydia trachomatis infection.

PROBLEM: Despite abundant reports on the risk role of uterine outflow tract obstruction in endometriosis, information on the occurrence of endometriosis in women with Chlamydia trachomatis infection causing fallopian tube obstruction is unknown. We investigated the role of Chlamydia trachomatis infection with or without fallopian tubal patency in the occurrence of endometriosis. METHODS: This is a retrospective case-controlled cohort study with 539 women who had laparoscopic surgery for several indications during the period between January, 2003 and June, 2010. Women with ectopic pregnancy, uterine anomaly, chromosomal abnormality, primary amenorrhea, and perimenopausal women were excluded. Endometriosis was diagnosed by laparoscopic inspection and confirmed by histopathology. Tubal patency was diagnosed by HSG or laparoscopic chromopertubation test. Presence of chlamydia infection was examined by RT-PCR and serological test. RESULTS: Two-hundred and seven women were enrolled. Eighty-six (41.5%) women had chlamydia infection. Tubal patency and occurrence of endometriosis were significantly decreased among women with chlamydia infection comparing to women without it (P = .005 and P = .0008, respectively). Even among women with patent tube, laparoscopic detection of endometriosis was significantly decreased in chlamydia infected comparing to non-infected women (P = .02). Multiple logistic regression model revealed that previous history of chlamydia infection significantly decreased the occurrence of endometriosis, and was independent of age, menstrual status, parity and tubal patency (odds ratio .44; 95% confidence interval .24-.80; P = .007). CONCLUSION: A decreased occurrence of peritoneal endometriosis was observed in women with Chlamydia trachomatis infection. The possible impairment of retrograde menstrual flow by chlamydia-infected tubal damage may decrease the risk of endometriosis.

AMH Concentrations in Peritoneal Fluids of Women With and Without Endometriosis.

Background: As its name indicates, anti-Müllerian hormone (AMH) is primarily found as an inhibitor of the Müllerian duct in male fetus. On the other hand, AMH may act as a mediator of Müllerian duct-derived female tissue, such as endometrium in normal and pathological conditions. However, the role of AMH in the functional regulations of endometriosis is not well understood. It can be hypothesized that AMH in peritoneal fluids may affect the activity of peritoneal endometriosis. In this study, we investigated the levels of AMH in peritoneal fluids (PF) in women with and without endometriosis. Methods: PF were collected during laparoscopy from 90 women diagnosed as having advanced endometriosis (rASRM stage III, n = 30; stage IV, n = 60), and 32 women without endometriosis were served as control. Paired serum samples were also collected before the surgery. AMH in PF and serum were measured by ELISA. Individual clinical information was collected. AMH levels were compared according to the presence of endometriosis. The expression of AMHR2 in peritoneal endometriotic lesions obtained during laparoscopy was examined by immunohistochemistry. Results: AMH levels in PF were positively and significantly correlated with serum AMH levels in both women with and without endometriosis (R 2 = 0.17, P < 0.0001; R 2 = 0.30, P = 0.001, respectively). Serum AMH levels were inversely and significantly correlated with age in women with endometriosis (R 2 = 0.092, P = 0.004) and in control women without statistical significance (R 2 = 0.078, P = 0.12). AMH levels in PF were also inversely but not significantly correlated with age in women with and without endometriosis (R 2 = 0.029, P = 0.11 and R 2 = 0.027, P = 0.37, respectively). Mean age and serum AMH levels were not significantly different between two groups. On the other hand, AMH levels in PF were significantly lower in women with endometriosis compared to those of control women [2.15 ± 2.13 (mean ± SD) vs. 4.40 ± 4.77 ng/mL, P = 0.0001]. AMHR2 are localized at glandular epithelium and stromal cells in the ectopic endometrium of peritoneal endometriosis. Conclusions: Women with endometriosis may present lower PF AMH levels even if they retain serum levels similar to women without disease. As peritoneal endometriosis expresses a specific receptor for AMH, lower AMH levels in PF of women with advanced endometriosis may be involved in the pathophysiology of peritoneal endometriosis.

Ovarian reserve after three-step laparoscopic surgery for endometriomas utilizing dienogest: A pilot study.

PURPOSE: Surgery for endometriomas may cause detrimental effects on ovarian reserve. We evaluated the safety of three-step laparoscopic surgery for endometriomas utilizing dienogest in terms of post-surgical ovarian reserve. METHODS: Twelve women received first look laparoscopy (FLL) with fenestration and drainage. Immediately after the surgery, they took oral dienogest 2 mg for three months; then, they received second look laparoscopy (SLL) with cystectomy. We compared serum AMH levels between women had three-step management with dienogest, and another twelve women had conventional one-step surgery without medications. In women had three-step procedures, the changes in concentration of proinflammatory cytokines and chemokines in peritoneal fluids were evaluated. RESULTS: Serum AMH levels were significantly decreased after three months of dienogest following FLL. AMH levels were also significantly decreased 3-6 months both after SLL and after one-step surgery; however, recovery of serum AMH levels at 9-12 months after surgery was evident in women had three-step surgery comparing to those of one-step surgery. Proinflammatory cytokines and chemokines in peritoneal fluids were downregulated at the time of SLL comparing to those of FLL. CONCLUSIONS: Three-step surgery with dienogest may be a beneficial approach to protect ovarian reserve. Dienogest may exert its effects in part by lowering proinflammatory cytokines and chemokines.

Significance of p53-Binding Protein 1 Nuclear Foci in Cervical Squamous Intraepithelial Lesions: Association With High-Risk Human Papillomavirus Infection and P16INK4a Expression.

As p53-binding protein 1 (53BP1) localizes to the sites of DNA double-strand breaks and rapidly forms nuclear foci (NF), and its presence may be an indicator of endogenous genomic instability (GIN). We previously showed that 53BP1 NF in cervical cells increase with neoplastic progression, indicating the significance of 53BP1 expression for the estimation of malignant potential during cervical carcinogenesis. This study aimed to further elucidate the impact of 53BP1 expression as a biomarker for cervical squamous intraepithelial lesion (SIL). A total of 81 tissue samples, including 17 of normal cervical epithelium, 22 of cervical intraepithelial neoplasia (CIN) 1, 21 of CIN2, and 21 of CIN3, from patients positive for high-risk human papillomavirus (HR-HPV) were used for double-label immunofluorescence of 53BP1 and Ki-67/p16INK4a expression and HR-HPV in situ hybridization. We analyzed associations between 53BP1 expression type with parameters such as CIN grade, HR-HPV infection status, p16INK4a expression, and CIN prognosis. Expression type of 53BP1 was significantly associated with histological grade of CIN and HR-HPV in situ hybridization signal pattern (P < .0001). There was a significant correlation between 53BP1 and p16INK4a expression levels (r = .73, P < .0001). However, there was no association between 53BP1 expression type and CIN prognosis. We propose that 53BP1 expression type is a valuable biomarker for SIL, which can help estimate the grade and GIN of cervical lesions reflecting replication stress caused by the integration of HR-HPV to the host genome.

Comprehensive immune complexome analysis detects disease-specific immune complex antigens in seminal plasma and follicular fluids derived from infertile men and women.

BACKGROUND: Autoimmune reactions and subsequent inflammation may underlie spermatogenic dysfunction and endometriosis-related infertility. The aim of this study is to identify disease-specific antigens in immune complexes (ICs) in seminal plasma (SP) and in follicular fluid (FF). METHODS: Immune complexome analysis, in which nano-liquid chromatography-tandem mass spectrometry is employed to comprehensively identify antigens incorporated into ICs in biological fluids, was performed for specimens collected from infertile couples undergoing assisted reproduction. Forty-two male patients consisting of subjects with oligozoospermia (n = 6), asthenozoospermia (n = 8), and normal semen analysis (n = 28). Fifty-eight female patients consisting of subjects with ovarian endometriosis (n = 10) and control women without disease (n = 48). RESULTS: Four disease-specific antigens were identified in subjects with oligozoospermia, while five disease-specific antigens were detected in subjects with asthenozoospermia, some of which are involved in sprematogenesis. Eight antigens were detected only in subjects with endometriosis. CONCLUSION: Functional characteristics of disease-specific antigens were found to correspond to the pathogenesis of male and female infertility. The formation of ICs may contribute to spermatogenic dysfunction and endometriosis-related infertility via loss of function of the related proteins. Immune complexome analysis is expected to be a valuable tool for the investigation of novel diagnostic methods and treatment strategies for infertility.

Fertility preservation in adolescent and young adult cancer patients: From a part of a national survey on oncofertility in Japan.

PURPOSE: This study evaluated the current status of reproductive disorders and provision of information on oncofertility to female adolescent and young adult (AYA) cancer patients in Japan. METHODS: A national survey of AYA cancer survivors was conducted. Children were <15 years old, and AYAs were 15-39 years old. Results from the survivors of other than gynecological disease who underwent chemotherapy were analyzed. RESULTS: Among the survivors, 41.4% were concerned about their reproductive function and infertility, and 36.2% were aware of menstrual cycle abnormalities. Among them, 15.5% (n = 20) of all and 21.2% (n = 17) of the AYA-onset survivors suffered infertility due to chemo- or radiotherapy and gave up childbearing. These rates were significantly higher than those of healthy AYAs. Although 80.8% of AYA-onset survivors answered that they had received information on reproductive function and infertility, only 55.8% had received information on fertility preservation methods. Furthermore, only 22.4% of all and 42.3% of AYA-onset survivors had received pretreatment information on fertility preservation methods. CONCLUSIONS: Not a few AYA cancer survivors reported reproductive dysfunction. These findings indicate that information provided on therapy-related problems before cancer treatment in Japan was insufficient and highlight the need to improve patient decision-making and support systems for fertility preservation.

Problems of reproductive function in survivors of childhood- and adolescent and young adult-onset cancer revealed in a part of a national survey of Japan.

PURPOSE: This study aimed to evaluate the current status of reproductive disorders as long-term complications in adolescent and young adult (AYA) cancer patients by comparing survivors of childhood-onset with those of AYA-onset cancer in Japan. METHODS: We conducted a national survey of AYA cancer survivors and healthy AYAs and analyzed the results from survivors who underwent chemotherapy and reported fertility problems as their current concern. RESULTS: Among all of the childhood-onset survivors, 27 (35.5%; nine males [28.1%] and 18 females [40.9%]) listed reproduction fertility problems as their current concern. Among all AYA-onset survivors, 25 (69.5%; 1/4 males [25.0%] and 24/32 females [75.0%]) listed these problems as a current concern. In contrast, 96.3% (26/27) of all childhood-onset cancer survivors and 68.0% (17/25) of all AYA-onset cancer survivors who received chemotherapy listed these problems as a current concern. CONCLUSIONS: A considerable number of both childhood-onset and AYA-onset cancer survivors, and especially those who had undergone chemotherapy, reported reproductive dysfunction as a delayed complication. It is vitally important to establish a supportive care system both for the patients whose fertility was abolished after the completion of cancer treatment and prophylactically for patients before they begin treatment.

[Current Status of Oncofertility in Adolescent and Young Adult (AYA) Generation Cancer Patients in Japan - National Survey of Oncologists].

A national survey conducted in 2016 aimed to evaluate the current status and needs of the field of oncofertility and to consider optimized medical delivery systems. A total of 739 oncologists, excluding gynecological and urological specialists, were surveyed. Of these, 99.2% thought that providing information on fertility preservation was important. Of the surveyed oncologists, 48% were affiliated with facilities providing assisted reproductive technology, and 79.3% practiced in university hospitals. Of 238 (32.2%) specialists who provided information on the risk of reproductive damage resulting from treatment in their facility, 163 (44.9%) and 75 (19.9%) practiced in university hospitals (n=363) and non-university hospitals (n= 376), respectively. In contrast, 14.3% and 32.7% of oncologists who practiced in university hospitals and non-university hospitals, respectively, collaborated with local obstetricians and gynecologists. Among oncologists who use a gradually expanding regional oncofertility network, 0.6% practice in university hospitals and 2.7% practice in non-university hospitals. Patients were advised that the risk of infertility was 92.3% and the likelihood of fertility preservation was 66.9%. Furthermore, as an ideal way of providing information on preservation of fertility, 22.9% of oncologists collaborate with local gynecologists, and 26.3% do so at a public cancer and reproductive medical counseling center. In addition, 34.7% and 55.1% of oncologists at university and non-university hospitals, respectively, thought that implementation of a fertility preservation program at a public facility would be desirable. Although most oncologists recognize the importance of providing information on reproductive medicine, the support system for reproductive function and fertility in adolescent and young adult (AYA) generation cancer patients is limited because of the lack of agreement on patient referral. The limited number of referrals in turn limits data collection in the field of oncofertility. Grant: A Health and Labour Sciences Research Grant: H27-Cancer Control-Ippan.

Effect of a gonadotropin-releasing hormone analog for ovarian function preservation after intravenous cyclophosphamide therapy in systemic lupus erythematosus patients: a retrospective inception cohort study.

OBJECTIVE: To determine the effect of leuprolide acetate, a synthetic gonadotropin-releasing hormone analog (GnRH-a) on ovarian function preservation in systemic lupus erythematosus (SLE) patients treated with cyclophosphamide (CYC) in clinical practice. METHODS: We enrolled 30 premenopausal female SLE patients who fulfilled the 1997 American College of Rheumatology revised criteria and were treated with intravenous CYC (IVCY) in 2008-2017. We used Kaplan-Meier survival estimates to compare the GnRH-a-treated patients and those not treated with GnRH-a as controls. We performed Cox regression analyses to identify factors associated with premature ovarian failure (POF), incidences of cardiovascular events, strokes and osteoporosis after IVCY therapy. RESULTS: After a mean follow-up of 41 months, POF developed in one of the 16 GnRH-a-treated patients (6%) versus seven of the 14 controls (50%). Significantly improved cumulative ovarian protection over time was observed in the GnRH-a-treated group (P = 0.030). The hazard model analysis showed that treatment with GnRH-a during IVCY therapy is an independent factor associated with POF after IVCY therapy (adjusted hazards ratio = 0.12, 95% CI 0.01-0.67, P = 0.013) but not incidences of cardiovascular events, strokes or osteoporosis. CONCLUSION: The combined use of GnRH-a with IVCY therapy was associated with a significant reduction of POF among premenopausal women with SLE, suggesting that the addition of GnRH-a can be a strategy to prevent POF among premenopausal women with SLE after IVCY therapy.

Bacterial contamination hypothesis: a new concept in endometriosis.

BACKGROUND: Endometriosis is a multifactorial disease that mainly affects women of reproductive age. The exact pathogenesis of this disease is still debatable. The role of bacterial endotoxin (lipopolysaccharide, LPS) and Toll-like receptor 4 (TLR4) in endometriosis were investigated and the possible source of endotoxin in the pelvic environment was examined. METHODS: The limulus amoebocyte lysate test was used to measure the endotoxin levels in the menstrual fluid and peritoneal fluid and their potential role in the growth of endometriosis was investigated. Menstrual blood and endometrial samples were cultured for the presence of microbes. The effect of gonadotrophin-releasing hormone agonist (GnRHa) treatment on intrauterine microbial colonization (IUMC) and the occurrence of endometritis was investigated. MAIN FINDINGS RESULTS: Lipopolysaccharide regulates the pro-inflammatory response in the pelvis and growth of endometriosis via the LPS/TLR4 cascade. The menstrual blood was highly contaminated with Escherichea coli and the endometrial samples were colonized with other microbes. A cross-talk between inflammation and ovarian steroids or the stress reaction also was observed in the pelvis. Treatment with GnRHa further worsens intrauterine microbial colonization, with the consequent occurrence of endometritis in women with endometriosis. CONCLUSION: For the first time, a new concept called the "bacterial contamination hypothesis" is proposed in endometriosis. This study's findings of IUMC in women with endometriosis could hold new therapeutic potential in addition to the conventional estrogen-suppressing agent.

Two consecutive successful live birth in woman with 17α hydroxylase deficiency by frozen-thaw embryo transfer under hormone replacement endometrium preparation.

17α-Hydroxylase deficiency is rare autosomal recessive disorder that manifested by hypertension, hypokalemia, delayed sexual development, primary amenorrhea and infertility. The information regarding infertility care and conception in women with this disorder are extremely limited. We report a 24-year-old Japanese woman with primary amenorrhea who was diagnosed as partial 17α-hydroxylase deficiency caused by homozygous 3 bp deletion in exon 1 of 17α-hydroxylase gene. In vitro fertilization with controlled ovarian stimulation was carried out and all viable embryo were frozen. During ovarian stimulation, serum progesterone levels were markedly elevated, and endometrial growth was impaired. Utilizing frozen-thaw embryo transfer under hormonal replacement (glucocorticoid, estradiol and progesterone), she had successfully given two consecutive live birth. Women with 17α-hydroxylase deficiency with residual ovarian reserve can afford reproductive success by appropriate diagnosis and treatment by assisted reproductive technology.

Association between ovarian endometrioma and ovarian reserve.

Endometrioma is one of the main pathologies of endometriosis, though its pathogenesis still remains enigmatic. Ovarian reserve is defined as the number and quality of the follicles left in the ovary at any given time. The cause of infertility in women with endometriosis is multifactorial. Diminished ovarian reserve is major concern in women with endometriosis-associated infertility. Cystectomy for endometriomas could negatively impact on post-operative ovarian reserve. Some women had surgery for endometriomas suffer from poor ovarian response, which directly affects treatment results. In addition, endometriomas themselves may be a cause of diminished ovarian reserve. Destruction of normal histological structure in ovarian cortex may affect dormancy of primordial follicles. Therefore, determination of ovarian reserve may serve as an important role in the management of reproductive health of women with endometriosis. Although the knowledge on the physiology of follicular development and mechanism of maintenance of ovarian reserve are rapidly accumulating, results obtained by ovarian reserve testing after surgery should be carefully evaluated according to the time-points and selected test. Further investigation on this issue is warranted.