Functional genomics analysis identifies loss of HNF1B function as a cause of Mayer-Rokitansky-Küster-Hauser syndrome.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital condition characterized by aplasia or hypoplasia of the uterus and vagina in women with a 46,XX karyotype. This condition can occur as type I when isolated or as type II when associated with extragenital anomalies including kidney and skeletal abnormalities. The genetic basis of MRKH syndrome remains unexplained and several candidate genes have been proposed to play a role in its etiology, including HNF1B, LHX1 and WNT4. Here, we conducted a microarray analysis of 13 women affected by MRKH syndrome, resulting in the identification of chromosomal changes, including the deletion at 17q12, which contains both HNF1B and LHX1. We focused on HNF1B for further investigation due to its known association with, but unknown etiological role in, MRKH syndrome. We ablated Hnf1b specifically in the epithelium of the Müllerian ducts in mice and found that this caused hypoplastic development of the uterus, as well as kidney anomalies, closely mirroring the MRKH type II phenotype. Using single-cell RNA sequencing of uterine tissue in the Hnf1b-ablated embryos, we analyzed the molecules and pathways downstream of Hnf1b, revealing a dysregulation of processes associated with cell proliferation, migration and differentiation. Thus, we establish that loss of Hnf1b function leads to an MRKH phenotype and generate the first mouse model of MRKH syndrome type II. Our results support the investigation of HNF1B in clinical genetic settings of MRKH syndrome and shed new light on the molecular mechanisms underlying this poorly understood condition in women's reproductive health.

Medical Management of Endometriosis in Adolescent and Young Adult Women: A Review of 91 Cases of Biopsy-Confirmed Endometriosis.

OBJECTIVES: To characterise contemporary trends in the hormonal management of endometriosis in adolescent and young adult patients with biopsy-proven endometriosis. METHODS: Retrospective chart review of women aged 14-25 years who underwent laparoscopy for pelvic pain with biopsy-proven endometriosis between January 2011 and September 2020 at an academic tertiary hospital system. The final sample included 91 patients with biopsy-confirmed endometriosis. RESULTS: Combined oral contraceptives (COCs) were the most common initial treatment (64% of patients). Progestin-only formulations (low- and high-dose norethindrone acetate) were offered to younger patients (age 15.9 ± 2.7 years) than those offered COCs (19.9 ± 3.3 years) and levonorgestrel intrauterine devices (LNG-IUDs) (21.9 ± 1.7 years). Current treatments varied widely and included COCs (32%), LNG-IUDs (18%), oral progestins (low- and high-dose norethindrone, medroxyprogesterone) (14%), elagolix (9%), and leuprolide (8%). Oral adjuncts to LNG-IUD were common: usually low- or high-dose norethindrone (37% of patients with an LNG-IUD), but also included progesterone, COCs, and elagolix. CONCLUSIONS: Oral progestins, LNG-IUDs, and COCs were the mainstay of initial treatment. Subsequent treatments varied widely and included COCs, LNG-IUDs, oral progestins, elagolix, leuprolide, and combinations of these agents. We observed that most young women switched between therapies, suggesting that a personalised approach is often used to determine treatment plans among the wide range of options currently available. This study helps define the spectrum of treatment regimens for endometriosis in adolescent females.

Reduction in Unindicated Cervical Cancer Screening in Adolescents in a Large Health Care System.

OBJECTIVES/PURPOSE: Evidence-based guidelines recommend against screening for cervical cancer (Pap testing) in average-risk adolescents <21 years old. Despite this, many still undergo unindicated screenings with subsequent detrimental reproductive health and economic consequences. Our aim was to reduce unindicated cervical cancer screening in individuals <21 years old in a large health care system by utilizing an electronic provider notification. METHODS: Starting in July 2020, a Best Practice Advisory (BPA) appeared in the electronic medical record (EMR) if providers ordered Pap testing on individuals <21 years old. This BPA reiterated that screening was not indicated for average-risk adolescents and prompted users to choose an indication if they wanted to proceed.A retrospective chart review, pre/post intervention study was performed comparing individuals <21 years old with Pap testing performed before and after intervention (January 2019-June 2020 and July 2020-June 2021, respectively). Patient characteristics were extracted from the EMR and analyzed using Fisher exact tests, Kruskal-Wallis tests, and logistic regression. RESULTS: There were 140 subjects included: 106 preintervention and 34 postintervention. There were no differences in baseline characteristics. Neither Pap nor human papillomavirus testing results differed between the groups. Preintervention, 6.6% of cytology tests were indicated compared to 20.6% postintervention ( p = .042). The proportion of indicated human papillomavirus testing did not differ preintervention and postintervention at 65% and 45%, respectively ( p = .295). The overall reduction in unindicated cervical cancer screening postintervention was 13.9% (95% CI = 4.0-23.7). CONCLUSIONS: We demonstrated that incorporating a BPA to the EMR reduces unindicated cervical cancer screening.

Diagnostic and surgical approaches to congenital uterine anomalies for the minimally invasive gynecologic surgeon.

PURPOSE OF REVIEW: Congenital uterine anomalies (CUAs) impact the physical and psychosocial wellbeing of affected patients. Managing these conditions depends on the clinical scenario, and in some cases, can involve the use of minimally invasive surgical techniques. The purpose of this review is to provide an update of the diagnosis, perioperative considerations, and treatment of CUAs. RECENT FINDINGS: The American Society for Reproductive Medicine (ASRM) updated the guidelines for classification of CUAs to provide practitioners with a standardized classification system and have created an interactive tool designed for provider use. SUMMARY: Gynecologic surgeons are likely to encounter CUAs during their career. This review provides updated guidance for the workup and treatment of CUAs.

Systematic Literature Review of Pediatric Male and Female Genital Hair Thread Tourniquet Syndrome.

OBJECTIVE: The aim of this study was to describe genital hair thread tourniquet syndrome (HTTS) and its treatment by pediatric and adolescent health care providers through a systematic literature review. METHODS: We performed a systematic literature review on pediatric male and female genital HTTS. Studies were included if they involved genital HTTS in males or females 21 years and younger and were published in English. The main outcomes were body parts involved, symptoms, treatment, anesthetic type, providers involved in diagnosis and management, and implications of delayed or missed diagnosis. RESULTS: There were 38 female cases from 33 publications (1973-2020) and 147 male cases from 47 publications (1951-2019). The average age among females and males was 9.1 and 5.1 years, respectively. Among cases involving female patients, 93% of them were premenarchal; patients were circumcised in 90% of reviewed cases of male HTTS. The most commonly involved body parts were clitoris and labia minora in females, and penis and urethra in males. Males most commonly presented with edema and urinary symptoms, whereas females most commonly presented with edema and pain. General anesthesia was used for tourniquet excision in most cases. Male and female genital HTTS were mostly managed by urologists and emergency medicine physicians, respectively. CONCLUSION: This systematic literature review of more than 150 cases of male and female genital HTTS describes evaluation and management of genital HTTS spanning 7 decades. The main treatment of genital HTTS remains prompt diagnosis and removal of the tourniquet, as well as education on prevention strategies. Delayed diagnosis due to lack of recognition of the HTTS can lead to serious sequelae. Development of national guidelines regarding best practices in management of genital HTTS disseminated to all providers taking care of pediatric and adolescent patients will lead to improved patient care.

The SWIFT Model for Lichen Sclerosus Among Premenarchal Girls.

OBJECTIVE/PURPOSE: Delay in diagnosis of childhood lichen sclerosus (LS) can be ameliorated with an efficient evaluation tool. We sought to create a useful prognostic tool for rapid and accurate risk stratification for LS in premenarchal girls. METHOD: We conducted a retrospective chart review at a single institution of premenarchal girls presenting with vulvovaginal complaints at a specialty pediatric and adolescent gynecology clinic at a major academic center. Sixty-nine patients seen between July 2019 and September 2020 were used as a pilot study to create a model for LS based on 18 signs and symptoms. Accuracy of the pilot model was confirmed in a larger data set (additional 105 patients, seen between January 2017 and December 2020), and model parameters were refined through cluster-based analytics. RESULTS: Pilot study yielded 5 predictors for LS: soreness (S), whitening (W), urinary incontinence (I), fissures (F), and thickening of the clitoral hood (T)-SWIFT. The final refined model is given as log odds (LS) = -7 + 3·S + 17·W + 3·I + 3·F + 18·T. This model yielded a >97% accuracy in predicting LS among 174 unique patients (LS prevalence = 18%). CONCLUSIONS: The SWIFT model accurately predicts clinical diagnosis of LS in premenarchal girls. Replication in other patient populations is highly encouraged. Awareness of LS is paramount, and an efficient, accurate evaluation tool will prove invaluable in assuring timely diagnosis and treatment for premenarchal patients.

Unindicated cervical cancer screening in adolescent females within a large healthcare system in the United States.

BACKGROUND: Current consensus recommendations are to not initiate cervical cancer screening for immunocompetent adolescent females before 21 years of age. This is in part because of the very low rate of 0.8 per 100,000 new cervical cancer cases diagnosed among women aged between 20 to 24 years. Timely human papillomavirus vaccination further decreases the incidence of cervical cancer to 4 cases per 100,000 persons by the age of 28 years. Screening before 21 years of age has demonstrated no clear benefit in cancer risk reduction or outcomes. In addition, unindicated screening among adolescents can lead to patient harm and increasing costs to the healthcare system. OBJECTIVE: It is important to assess the rates of overutilization of cervical cancer screening and to identify areas where improvements have occurred and where further opportunities exist. This study aimed to assess the trends over time and the practice and provider factors associated with unindicated cervical cancer screening tests in adolescent females within the largest healthcare system in the state. STUDY DESIGN: Cross-sectional data from patients aged 13 to 20 years who underwent cervical cancer screening between January 1, 2012, and December 31, 2018, across a large multihospital health system were reviewed. All cervical cancer screening results were included. The incidence rate of unindicated screening was analyzed over 6-month intervals using the Poisson regression analysis. RESULTS: The study included data from 118 providers and 794 women. Among the 900 screening results, most (90%) were unindicated: 87% with unindicated cytology testing alone and 14% with unindicated human papillomavirus testing. Screening tests were collected from patients aged 13 to 20 years, many of whom had multiple unindicated cytology tests, with 25 patients having ≥3 tests before the age of 21 years. Most results of cytology testing were negative for intraepithelial lesion or malignancy (77%). Moreover, 52 invasive diagnostic or therapeutic procedures (49 colposcopies and 3 conizations) were performed, of which 45 (87%) followed an unindicated screening test. Between 2012 and 2018, the incidence rate of unindicated cytology decreased by 33% (12.6 to 8.5 unindicated cytology per 1000 encounters). The incidence rate of unindicated screening was lower in the academic setting than in the community setting (incidence rate ratio, 0.43; P<.01). Even with decreases in the overall rates of unindicated screening throughout the study period, there were still 58 unindicated screening tests performed in the final year of this study. CONCLUSION: Despite substantial reductions in unindicated screening for women aged <21 years, there remained areas for improvement. Our data reflected practices of guideline nonadherence up to 7 years after the 2012 guideline. Now, with a new series of changes to the guidelines, which may be even more challenging for patients and providers, it is more important than ever to utilize evidence-based strategies to improve guideline dissemination and adherence.

Characteristics Among Premenarchal Girls With Lichen Sclerosus.

OBJECTIVES: Lichen sclerosus (LS), a chronic inflammatory dermatosis localized in the anogenital region, is known to be associated with lower urinary tract symptoms (LUTS) in postmenopausal women; however, there is a paucity of data on prepubertal girls. We sought to characterize the relationship between LS, LUTS, and constipation among premenarchal girls. MATERIALS AND METHODS: We conducted a retrospective chart review of premenarchal girls presenting at the pediatric adolescent gynecology and pediatric urology clinics at our institution diagnosed with vulvar LS during a 4-year period. Demographics, clinical presentation, time from onset of urinary and/or bowel symptoms to LS diagnosis, and treatment response were assessed. Analysis was completed using median, range, and nonparametric statistical analysis where appropriate. RESULTS: Nineteen premenarchal girls with LS met inclusion criteria. The median age at LS diagnosis was 6.2 years (range = 3.3-13.3 yrs). Most girls (12/19, 63.2%) presented with LUTS during LS evaluation, and 11 (57.9%) of 19 patients had constipation. Pruritus and hypopigmentation were the most frequently encountered LS symptom and sign, respectively. Fourteen (73.7%) of the 19 girls had resolution/improvement of LS symptoms after LS treatment. Of the 12 patients with LUTS, 7 (58.3%) had resolution/improvement of LUTS symptoms, 3 (25.0%) had unchanged voiding symptoms, and 2 (16.7%) had unknown changes. CONCLUSIONS: Although further studies are needed to better characterize the relationship between LUTS, constipation, and LS, our findings suggest that premenarchal subjects presenting with LUTS should be assessed for LS. Likewise, patients presenting with LS should be assessed for LUTS and constipation.

The Embryological Landscape of Mayer-Rokitansky-Kuster-Hauser Syndrome: Genetics and Environmental Factors.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a disorder caused by Müllerian ducts dysgenesis affecting 1 in 5000 women with a typical 46,XX karyotype. The etiology of MRKH syndrome is complex and largely unexplained. Familial clustering suggests a genetic component and the spectrum of clinical presentations seems consistent with an inheritance pattern characterized by incomplete penetrance and variable expressivity. Mutations of several candidate genes have been proposed as possible causes based on genetic analyses of human patients and animal models. In addition, studies of monozygotic twins with discordant phenotypes suggest a role for epigenetic changes following potential exposure to environmental compounds. The spectrum of clinical presentations is consistent with intricate disruptions of shared developmental pathways or signals during early organogenesis. However, the lack of functional validation and translational studies have limited our understanding of the molecular mechanisms involved in this condition. The clinical management of affected women, including early diagnosis, genetic testing of MRKH syndrome, and the implementation of counseling strategies, is significantly impeded by these knowledge gaps. Here, we illustrate the embryonic development of tissues and organs affected by MRKH syndrome, highlighting key pathways that could be involved in its pathogenesis. In addition, we will explore the genetics of this condition, as well as the potential role of environmental factors, and discuss their implications to clinical practice.

The association between anti-Müllerian hormone and vitamin 25(OH)D serum levels and polycystic ovarian syndrome in adolescent females.

BACKGROUND: High anti-Müllerian hormone (AMH) levels and 25-hydroxyvitamin D [25(OH)D] deficiency have been associated with polycystic ovarian syndrome (PCOS) in adult women, and implicated in its pathogenesis. Herein we determined if the level of both AMH and 25(OH)D are altered in adolescent females with clinical features of PCOS. METHODS: This is a cross-sectional study utilizing a retrospective chart review of 128 patients aged 12-20 referred to an academic adolescent gynecology and endocrinology clinic for an evaluation of suspected PCOS. Unadjusted comparisons of AMH and 25(OH)D distributions between subjects with and without PCOS were performed using the Wilcoxon Rank Sum test. Quantile regression was used to compare the median AMH and 25(OH)D between subject groups; adjusting for race, ethnicity, BMI, insurance type, age, and season when bloodwork was performed. RESULTS: Seventy-four subjects were classified as having PCOS by meeting ≥2 of the three Rotterdam diagnostic criteria, and 47 subjects met only one Rotterdam diagnostic criteria, and were used as the comparative non-PCOS group. There were statistically significant unadjusted differences in median levels of AMH and 25(OH)D. In the adjusted analyses, median AMH was significantly higher in the PCOS group compared to the non-PCOS group (+ 2.39 ng/mL, 95% CI 0.43, 4.35, p = 0.018); 25(OH)D was significantly lower in the PCOS group (- 9.01 ng/mL, 95% CI -14.49, - 3.53 p = 0.001). In our sample, adolescents in both groups had insufficient 25(OH)D level (22 ng/mL) and elevated BMI (32.2 kg/m2). CONCLUSIONS: Adolescents with PCOS display high levels of AMH and low 25(OH)D levels. Since traditional clinical markers of PCOS may be physiologic in adolescents, AMH and 25(OH)D may be used as surrogate markers of PCOS risk in adolescents.

The complex relationship between urinary and defecatory disorders in young and adolescent girls.

PURPOSE OF REVIEW: Scientific advancements have led to enhanced clarity about the interrelationship between urinary tract pathology and functional bowel disturbances. The present article will review the current literature regarding the cause, pathophysiology, diagnosis, and treatment of lower urinary tract dysfunction and abnormal bowel habits in young and adolescent girls. RECENT FINDINGS: Complex neurological, physiological mechanisms and functional behaviors exist that contribute to the development of coexisting urinary symptoms and defecatory disorders in young and adolescent girls. Bladder bowel dysfunction (BBD) in childhood and adolescence is carried into adulthood creating a lifetime health burden. SUMMARY: Practitioners should be aware and actively screen for conditions mimicking BBD with time-efficient and effective history-taking and physical exams that reduce anxiety and fear. The present review provides guide to comprehensive treatment strategies for managing complex pelvic floor disorders including urinary incontinence, defecatory disorders, pelvic and perineal pain, and constipation. More research is needed to elucidate pathophysiology and optimal treatment strategies of the BBD.

Assessment of a Novel Interactive Website to Inform Adolescent and Young Adult Decision-Making about Contraception.

STUDY OBJECTIVE: Adolescents and young adults (AYAs) rely on internet resources for sexual and reproductive health (SRH) information. Interactive tools are promising in health education, yet existing SRH websites do not contain validated resources to support AYAs in contraception decision-making. "Teen Health" is an original, interactive educational website designed for AYAs that includes a novel contraception education tool (CET). METHODS: A convenience sample of pregnancy-capable patients aged 13-25 years were recruited during scheduled appointments at outpatient clinics affiliated with a tertiary children's hospital from January to June 2022. Electronic surveys evaluated participants' contraception preferences before and after website exposure. CET results were reported in the post-website exposure survey. Written feedback was solicited after website exposure. RESULTS: One hundred and twenty-eight participants with a mean age of 15.95 years (SD 1.93) participated in this study. Participant demographic characteristics were notable for diverse representation of gender identities and sexual preferences. Contraception preferences before and after website exposure differed significantly (P < .001). Oral contraceptive pills were the most commonly selected contraception method both before and after website exposure. There was a significant relationship between CET results and post-website contraception preference. Many participants asked for additional topics in adolescent health to be featured on "Teen Health." CONCLUSION: This study demonstrates the feasible implementation and utility of an interactive, teen-friendly SRH educational tool for AYAs. Further study of this website's utility may include broadening the research population to include other languages, clinical institutions, and educational settings; non-contraceptive uses for this resource; and contraception selection outcomes after exposure to this website.

Impact of luteoma during pregnancy on fetal development and its long-term effects into adulthood.

A woman in her 30s presents to the Differences in Sexual Development Programme at a tertiary care academic medical centre with vaginal stenosis and scarring. Her medical history is significant for virilisation in utero due to a maternal luteoma of pregnancy. Laboratory investigations at the time of birth showed elevated androgens in both mother and daughter. During infancy, she underwent clitoroplasty and vaginoplasty for correction of posterior vaginal fusion. She represented as an adult with vaginal stenosis, with associated physical and psychosocial implications. She was not able to insert a tampon or have penetrative intercourse. After examination and shared decision-making, the patient underwent cystoscopy, vaginoscopy and posterior vaginoplasty with the goal to create a normal calibre vagina. Postoperative dilator use was recommended to prevent restenosis of the introitus. In clinic follow-up, the patient was observed to have a normal calibre vagina.

Ovarian Leydig Cell Tumor Associated with Recurrent Torsion and Virilization in an Adolescent Patient.

Ovarian tumors are rare in children; however, their incidence increases with age. Of these ovarian tumors, Leydig cell tumors are some of the rarest, accounting for less than 0.1% of all ovarian tumors across all ages. Leydig cell tumors predominantly occur in postmenopausal women and are characterized by nodular proliferation of Leydig cells in the ovarian hilum with intracytoplasmic Reinke crystals. These tumors secrete androgens, which can disrupt ovarian function, clinically presenting with abnormal uterine bleeding and virilization. Although they are generally benign, current recommendations are for treatment with a unilateral salpingo-oophorectomy. In adolescents, hyperandrogenism is most commonly caused by polycystic ovarian syndrome (PCOS); however, the differential for hyperandrogenism is broad. We present a case of a 15-year-old girl with a history of primary amenorrhea who presented with a Leydig cell tumor associated with recurrent ovarian torsion and virilization. This case reviews the challenges with diagnosis, management, and future implications of a rare androgen-secreting tumor in young patients.

Altered extracellular matrix dynamics is associated with insulin resistance in adolescent children with obesity.

OBJECTIVE: The objective of this study was to examine the hypothesis that abdominal and gluteal adipocyte turnover, lipid dynamics, and fibrogenesis are dysregulated among insulin-resistant (IR) compared with insulin-sensitive (IS) adolescents with obesity. METHODS: Seven IS and seven IR adolescents with obesity participated in a 3-h oral glucose tolerance test and a multi-section magnetic resonance imaging scan of the abdominal region to examine body fat distribution patterns and liver fat content. An 8-week 70% deuterated water (2 H2 O) labeling protocol examined adipocyte turnover, lipid dynamics, and fibrogenesis in vivo from biopsied abdominal and gluteal fat. RESULTS: Abdominal and gluteal subcutaneous adipose tissue (SAT) turnover rates of lipid components were similar among IS and IR adolescents with obesity. However, the insoluble collagen (type I, subunit α2) isoform measured from abdominal, but not gluteal, SAT was elevated in IR compared with IS individuals. In addition, abdominal insoluble collagen Iα2 was associated with ratios of visceral-to-total (visceral adipose tissue + SAT) abdominal fat and whole-body and adipose tissue insulin signaling, and it trended toward a positive association with liver fat content. CONCLUSIONS: Altered extracellular matrix dynamics, but not expandability, potentially decreases abdominal SAT lipid storage capacity, contributing to the pathophysiological pathways linking adipose tissue and whole-body IR with altered ectopic storage of lipids within the liver among IR adolescents with obesity.

A common curriculum in obstetrics and gynecology for medical students globally.

OBJECTIVE: Global variations in women's health outcomes, increased international migration, and an increase in the number of medical schools underpin the need for global standardization in obstetrics and gynecology curricula for medical students. However, there are currently no recommendations regarding the content of a common curriculum. The aim of this project was to agree the objectives for a common curriculum in obstetrics and gynecology for medical students globally. METHODS: The curriculum was developed and agreed by an international taskforce of obstetricians and gynecologists. Published curricula for medical students in a variety of regions globally were reviewed and discussed, and the objectives for a common curriculum in obstetrics and gynecology for medical students were agreed by consensus. RESULTS: The content of the proposed curriculum is classified into three domains: clinical skills, professional behaviors, and knowledge. The recommended curriculum covers health conditions that affect women globally in different social and cultural contexts, and addresses important global health issues of relevance to obstetrics and gynecology. CONCLUSION: The methods and outcomes of a project by an international taskforce of obstetricians and gynecologists to develop a common curriculum in obstetrics and gynecology for medical students globally are presented. More work is required to identify ways in which the curriculum may be adapted to a minimum essential required curriculum in times of man-made or natural disasters. Achieving these will facilitate the intended long-term aims of this curriculum, to improve women's health outcomes globally.

Vaginal bleeding in a newborn as initial presentation of uterus didelphys.

Vaginal bleeding of the newborn is described as a normal phenomenon, occurring physiologically in a subset of baby girls as a response to decreased oestrogen levels in the postnatal period compared with in utero exposure. Here, we present the case of heavy vaginal bleeding prompting an evaluation via transabdominal ultrasound, which was ultimately diagnostic for uterus didelphys. We suggest that neonates with uterus didelphys are predisposed to heavy bleeding due to relatively larger amount of the endometrial tissue in two cavities. While diagnosis of Müllerian anomalies is typically made in adulthood, an earlier diagnosis facilitates timely medical and surgical intervention and prompts screening for concurrent and associated conditions. In summary, we recommend routine consideration of transabdominal ultrasound to investigate abnormal vaginal bleeding in the newborn.