Study protocol for the implementation of Centering Patients with Fibroids, a novel group education and empowerment program for patients with symptomatic uterine fibroids.

BACKGROUND: Black women and people with uteri have utilized collectivistic and relational practices to improve health outcomes in the face of medical racism and discrimination for decades. However, there remains a need for interventions to improve outcomes of uterine fibroids, a condition that disproportionately impacts Black people with uteri. Leveraging personalized approaches alongside evidence that demonstrates the positive impact of social and peer support on health outcomes, we adapted from CenteringPregnancy, an evidence based group prenatal care intervention, for the education and empowerment of patients with uterine fibroids. METHODS: The present report provides  an overview of the study design and planned implementation of CPWF in cohorts at Boston Medical Center and Emory University / Grady Memorial Hospital. After receiving training from the Centering Healthcare Institute (CHI), we adapted the 10-session CenteringPregnancy curriculum to an 8-session hybrid group intervention called Centering Patients with Fibroids (CPWF). The study began in 2022 with planned recruitment of six cohorts of 10-12 participants at each institution. We will conduct a mixed methods evaluation of the program using validated survey tools and qualitative methods, including focus groups and 1:1 interviews. DISCUSSION: To date, we have successfully recruited 4 cohorts at Boston Medical Center and are actively implementing BMC Cohort 5 and the first cohort at Emory University / Grady Memorial Hospital. Evaluation of the program is forthcoming.

Fibroids are non-cancerous smooth muscle tumors that disproportionate impact black women and gender expansive people. Our team adapted CenteringPregnancy, a group based model of prenatal care, to an education and empowerment program for peple with fibroids called Centering Patients with Fibroids (CPWF). This paper describes the development and implemation of the program at two academic hospitals serving diverse patients in Boston, Massachusetts and Atlanta, Georgia. To evaluate the successes and challenges of the program, we ask participants to complete surveys to learn more about their experience with having fibroids and also invite them to group feedback sessions or focus groups. We also interview other healthcare providers, team members, and hospital leadership on their knowledge and thoughts about the program. We hope to use the feedback to improve the program and make it available to more people across the country.

OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity.

Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1-/- embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

Uterine fibroids and incidence of depression, anxiety and self-directed violence: a cohort study.

BACKGROUND: Depression and anxiety are prevalent among women with uterine fibroids (UF). The rate of mental health diagnoses in women with UF has not been studied. METHODS: Women aged 18-50 years with diagnosed UF were identified in the Optum Clinformatics commercial insurance claims database (OptumInsight, Eden Prairie, Minnesota) from 1 May 2000 to 31 March 2020 (n=313 754) and were matched 1:2 on age and calendar time to women without (n=627 539). Cox proportional hazards models estimated HRs and 95% CIs between UF and diagnosed depression, anxiety and self-directed violence, adjusting for demographics and comorbidities. Among women with diagnosed UF, the association between hysterectomy and mental health outcomes was estimated. RESULTS: After adjusting for confounders, women with diagnosed UF had a higher rate of depression (HR: 1.12; 95% CI 1.10 to 1.13), anxiety (HR: 1.12; 95% CI 1.10 to 1.13) and self-directed violence (HR: 1.46; 95% CI 1.29 to 1.64) than women without. Among women with pain symptoms and heavy menstrual bleeding, the HR comparing women with diagnosed UF to women without was 1.21 (95% CI 1.18 to 1.25) for depression, 1.18 (95% CI 1.15 to 1.21) for anxiety and 1.68 (95% CI 1.35 to 2.09) for self-directed violence. Among women with diagnosed UF, the HR comparing women who underwent a hysterectomy to women who did not was 1.22 (95% CI 1.17 to 1.27) for depression, 1.13 (95% CI 1.09 to 1.17) for anxiety and 1.86 (95% CI 1.39 to 2.49) for self-directed violence. CONCLUSIONS: Rates of depression, anxiety and self-directed violence were higher among women with diagnosed UF, particularly among those who experienced pain symptoms or who underwent hysterectomy.

Chlamydia trachomatis Infection, when Treated during Pregnancy, Is Not Associated with Preterm Birth in an Urban Safety-Net Hospital.

Preterm birth is a major public health problem, occurring in more than half a million births per year in the United States. A number of maternal conditions have been recognized as risk factors for preterm birth, but for the majority of cases, the etiology is not completely understood. Chlamydia trachomatis is one of the most prevalent sexually transmitted infections in the world. However, its role in adverse pregnancy outcome in women is still debated. In order to determine if genitourinary tract infection with C. trachomatis during pregnancy was associated with preterm birth, we conducted a case-control study on women who delivered at Boston Medical Center, an urban "safety-net" hospital that serves a socioeconomically disadvantaged and racially diverse population. Women with known risk factors for preterm birth or immune suppression were excluded. Variables collected on enrolled subjects included demographics; diagnosis of C. trachomatis during or prior to pregnancy; tobacco, alcohol, and illicit substance use; gestational age; and birthweight and gender of the newborn. We also collected urine for chlamydia testing at the time of delivery and placental biopsies for nucleic acid amplification and histological studies. A total of 305 subjects were enrolled: 100 who delivered preterm and 205 who delivered full term. Among those subjects, we identified 19 cases of pregnancy-associated C. trachomatis infection: 6/100 preterm and 13/205 full term, a difference which was not statistically significant. Only two cases of untreated chlamydia infection were identified postpartum, and both occurred in women who delivered at term. We conclude that genitourinary tract infection with C. trachomatis during pregnancy, when appropriately treated, is not associated with preterm birth.

Vaginal cuff dehiscence following transvaginal oocyte retrieval: a case report.

BACKGROUND: Vaginal cuff dehiscence (VCD) is a rare but potentially serious complication following hysterectomy with an estimated incidence of 0.14-1.4%. There is a wide range of risk factors thought to contribute to VCD, but due to its rare occurrence, much still remains to be learned about the true impact of risk factors leading to dehiscence. We present here the second known report of VCD to occur in a patient undergoing transvaginal oocyte retrieval during her fertility treatment. This case highlights what may become a more common clinical scenario as more premenopausal women are diagnosed with reproductive tract cancers and access assisted reproductive therapies to preserve fertility. CASE PRESENTATION: Our patient is a 35-year-old G1 P0 A1 who had undergone ovary-sparing total laparoscopic hysterectomy (TLH) following diagnosis of endometrial adenocarcinoma. She underwent two in-vitro fertilization (IVF) cycles after TLH to bank frozen blastocysts, the first vaginal oocyte retrieval (VOR) taking place 12 weeks following hysterectomy. She experienced VCD during her second VOR that occurred 17 weeks after TLH, the second case of VCD to be reported in the literature during fertility preservation treatment following hysterectomy. The patient underwent an emergent and uncomplicated repair of the defect vaginally the same day. CONCLUSIONS: Currently there are no guidelines in place for women who have undergone hysterectomy with regard to when they can begin fertility treatment in the post-operative period. Based on now two case reports, it is worth considering extension of the typical 6-week timeline of avoidance of vaginal procedures to allow for full cuff healing. Infertility providers should also be mindful of limiting transvaginal ultrasounds where possible to reduce force along the cuff.

Cost-effectiveness of preexposure prophylaxis for HIV prevention for conception in the United States.

OBJECTIVE: The aim of this study was to investigate the value of coformulated Tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) for preexposure prophylaxis (PrEP) for conception in the U.S. and to identify scenarios in which 'Undetectable = Untransmittable' (U = U) may not be adequate, and rather, PrEP or assisted reproduction would improve outcomes. DESIGN: We developed a Markov cohort simulation model to estimate the incremental benefits and cost-effectiveness of PrEP compared with alternative safer conception strategies, including combination antiretroviral therapy (cART) alone for the HIV-infected partner and assisted reproductive technologies. We modelled various scenarios in which HIV RNA suppression in the male partner was less than perfect. SETTING: U.S. healthcare sector perspective. PARTICIPANTS: Serodiscordant couples in the U.S. was composed of an HIV-infected male and HIV-uninfected female seeking conception. INTERVENTION: Economic analysis. MAIN OUTCOME MEASURE(S): Cumulative risks of HIV transmission to women and babies, maternal life expectancy, discounted quality-adjusted life years (QALY), discounted lifetime medical costs and incremental cost-effectiveness ratios. RESULTS: cART with condomless intercourse limited to ovulation was the preferred HIV prevention strategy among women seeking to conceive with an HIV-infected partner who is HIV-suppressed. PrEP was not cost-effective for women who had partners who were virologically suppressed. When the probability of male partner HIV suppression was low and we assumed generic pricing of PrEP, PrEP was cost-effective, and sometimes even cost-saving compared with cART alone. CONCLUSION: From a U.S. healthcare sector perspective, when the male partner was not reliably suppressed, PrEP became economically attractive, and in some cases, cost-saving.

Physician-scientists in obstetrics and gynecology: predictors of success in obtaining independent research funding.

BACKGROUND: Obstetrics and gynecology departments receive the smallest amount of National Institutes of Health research funding and have significantly lower application success rates compared to pediatric, internal medicine, and surgery departments. The development of mentored early career development training grants (K awards) has been one strategy implemented by the National Institutes of Health to help aspiring physician-scientists establish independent research careers. OBJECTIVE: The purpose of this study is to describe the cohort of obstetrics and gynecology physician-scientists who were K08, K12, and K23 recipients from 1988 through 2015 and to identify predictors of success in obtaining independent federal funding, as defined by acquisition of an R01, R21, R34, U01, U54, P01, or P50 award. We hypothesized that sex, subspecialty, type of K award, and dual MD/PhD would impact success rates. STUDY DESIGN: K08, K12, and K23 recipients from 1988 through 2015 were identified from the National Institutes of Health Research Portfolio Online Reporting Tools, the office of the National Institutes of Health Freedom of Information Act, and the website of the Reproductive Scientist Development Program. Data were stratified by sex, educational degree, subspecialty, and type of K award. Data were analyzed using the Pearson χ2 and Fisher exact tests. The Kaplan-Meier estimator was used to determine rates of conversion to independent funding over time. RESULTS: A total of 388 K recipients were identified. Women accounted for 66% of K awards while men accounted for 34%. Among K recipients, 82% were MDs, while 18% were MD/PhDs. K12 awards accounted for 82% of all K awards, while K08 and K23 awards accounted for 10% and 8%, respectively. Subspecialists in maternal-fetal medicine and reproductive endocrinology and infertility received the highest proportion of K awards, followed by generalists and gynecologic oncologists. Altogether, the 3 subspecialty groups accounted for 68% of all K awards. R01 awards made up the bulk of independent funding. Among recipients who received their first K award between 1988 and 2009, 63 of 288 (22%) were successful at obtaining an R01. Rates of R21 (n = 22), U01 (n = 15), U54 (n = 12), P01 (n = 5), R34 (n = 1), and P50 (n = 1) acquisition ranged from 0.35-7.6%. In all, 118 K scholars (41%) were successful at achieving independent funding of any type compared to 1219 of 7535 (16.2%) obstetrics and gynecology non-K scholars. K08 recipients received the largest proportion of R01 awards compared to K12 and K23 recipients (32% vs 20%; P = .12), while 21% of K12 recipients and 17% of K23 recipients achieved an R01. There were no differences in the rates of independent funding success among K12 programs. K23 recipients were more likely to obtain an R21 (22% vs 6%, P = .008) compared to K12 and K08 recipients. The mean time to R01 acquisition was 6.8 years, while the mean time to independent funding of any type was 6.4 years. There were no significant differences in independent funding success rates by sex, educational degree, or subspecialty, although generalists received the highest proportion of R01 awards (29%). CONCLUSION: Mentored early career development K programs enable aspiring obstetrics and gynecology physician-scientists to achieve higher rates of National Institutes of Health-based independent research funding compared to non-K recipients.

Brief Report: Cesarean Delivery and Subsequent Fecundability.

BACKGROUND: Studies have shown that cesarean delivery is associated with fewer subsequent births relative to vaginal delivery, but it is unclear whether confounding by pregnancy intention or indication for surgery explained these results. We evaluated the association between cesarean delivery and subsequent fecundability among 910 primiparous women after singleton live birth. METHODS: In a cohort of Danish women planning pregnancy (2007-2012), obstetrical history was obtained via registry linkage; time-to-pregnancy and covariate data were collected via questionnaire. Fecundability ratios (FRs) and 95% confidence intervals (CIs) were adjusted for potential confounders. RESULTS: Relative to spontaneous vaginal delivery, emergency cesarean delivery with cephalic presentation showed little association with fecundability (FR = 1.0, 95% CI = 0.83, 1.3), but cesarean delivery with breech presentation (FR = 0.72, 95% CI = 0.53, 0.97) and planned cesarean delivery with cephalic presentation (FR = 0.51, 95% CI = 0.25, 1.0) were associated with reduced fecundability. CONCLUSIONS: The cesarean-fecundability association varied by previous fetal presentation and emergency status.

History of uterine leiomyoma and risk of endometrial cancer in black women.

BACKGROUND: Previous studies have found an association between uterine leiomyomata (UL) and uterine malignancies. This relation has not been studied in black women, who are disproportionately affected by UL. METHODS: We investigated prospectively the association between self-reported physician-diagnosed UL and endometrial cancer in the Black Women's Health Study. During 1995-2013, 47,267 participants with intact uteri completed biennial health questionnaires. Reports of endometrial cancer were confirmed by pathology data from medical records and cancer registries. Cox regression was used to derive incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: There were 300 incident endometrial cancer cases during 689,546 person-years of follow-up. In multivariable models, UL history was associated with a 42% greater incidence of endometrial cancer compared with no such history (95% CI 1.12-1.80). IRRs for cancer diagnosed 0-2, 3-9, and ≥10 years after UL diagnosis were 3.20 (95% CI 2.06-4.98), 0.95 (95% CI 0.60-1.52), and 1.35 (95% CI 1.03-1.77), respectively. Stronger overall associations between UL history and endometrial cancer were observed for later stages at cancer diagnosis (IRR = 2.25, 95% CI 1.09-4.63) and type II/III cancers (IRR = 3.13, 95% CI 1.64-5.99). CONCLUSIONS: In this large cohort of black women, a history of UL was positively associated with endometrial cancer, particularly type II/III tumors. The strongest association was observed for cancer diagnosed within 2 years of UL diagnosis, a finding that might be explained by greater surveillance of women with UL or misdiagnosis of cancer as UL. However, an association was also observed for cancer reported ≥10 years after UL diagnosis.

Candidate gene analysis in a case of congenital absence of the endometrium.

BACKGROUND: Primary amenorrhea usually result from a genetic or anatomic abnormality. We present the first reported patient with the absence of endometrium and lumen in a small bicornuate uterus in a patient with primary amenorrhea. CASE PRESENTATION: A 41-year-old woman presented for evaluation of primary amenorrhea and infertility. She did develop normal secondary sexual characteristics but never had menses. Physical examination, hormone analyses, and karyotype analysis were normal. Transvaginal ultrasonography revealed a small uterus with absent endometrial stripe. Ovaries were normal in size. Pathology from hysterectomy for abnormal Pap smears revealed a hypoplastic bicornuate uterus with absence of lumen and absent endometrium. DNA analyses for mutations in the coding sequences of three members of HOXA gene family was performed, but no variants in the coding sequence of these genes were found. These findings support the hypothesis that mutations in the coding sequence of HOXA10, HOXA11, and HOXA13 are not responsible for congenital endometrial absence with bicornuate hypoplastic uterus. CONCLUSIONS: Congenital absence of the endometrium is an uncommon etiology for primary amenorrhea, and nonvisualization of the endometrial stripe on ultrasound imaging in association with primary amenorrhea should raise suspicion of this rare disorder in this case.

Dynamic kisspeptin receptor trafficking modulates kisspeptin-mediated calcium signaling.

Kisspeptin receptor (KISS1R) signaling plays a critical role in the regulation of reproduction. We investigated the role of kisspeptin-stimulated KISS1R internalization, recycling, and degradation in the modulation of KISS1R signaling. Kisspeptin stimulation of Chinese hamster ovary or GT1-7 cells expressing KISS1R resulted in a biphasic increase in intracellular Ca(2+) ([Ca(2+)]i), with a rapid acute increase followed by a more sustained second phase. In contrast, stimulation of the TRH receptor, another Gq/11-coupled receptor, resulted in a much smaller second-phase [Ca(2+)]i response. The KISS1R-mediated second-phase [Ca(2+)]i response was abolished by removal of kisspeptin from cell culture medium. Notably, the second-phase [Ca(2+)]i response was also inhibited by dynasore, brefeldin A, and phenylarsine oxide, which inhibit receptor internalization and recycling, suggesting that KISS1R trafficking contributes to the sustained [Ca(2+)]i response. We further demonstrated that KISS1R undergoes dynamic ligand-dependent and -independent recycling. We next investigated the fate of the internalized kisspeptin-KISS1R complex. Most internalized kisspeptin was released extracellularly in degraded form within 1 hour, suggesting rapid processing of the internalized kisspeptin-KISS1R complex. Using a biotinylation assay, we demonstrated that degradation of cell surface KISS1R was much slower than that of the internalized ligand, suggesting dissociated processing of the internalized kisspeptin-KISS1R complex. Taken together, our results suggest that the sustained calcium response to kisspeptin is dependent on the continued presence of extracellular ligand and is the result of dynamic KISS1R trafficking.

Tuboovarian abscess. Factors associated with operative intervention after failed antibiotic therapy.

OBJECTIVE: To evaluate whether size of tuboovarian abscess (TOA) and other clinical characteristics were associated with the need for surgical intervention. STUDY DESIGN: A retrospective chart review of patients hospitalized at an inner city hospital between January 1998 and December 2007 with the diagnosis of TOA. Demographics, medical history, clinical markers of infection, radiology, pathology, and operative reports were examined. Student's t test and Fisher's exact test were utilized to analyze differences between groups. Multiple logistic regression analysis was performed to identify significant predictors of surgery. Receiver operating characteristic (ROC) analysis was used to assess how well TOA size and other significant variables were associated with the need for operative or procedural intervention. RESULTS: A total of 163 patients with TOA were identified; 41 patients were excluded based on specific criteria. Of the remaining 122 women, 65.6% responded to antibiotic therapy, and 34.4% had surgery or ultrasound-guided drainage. Mean TOA size in the medical group was 4.4 cm as compared to 7.3 cm in the surgical group (p < 0.0001). Maximal leukocyte count, older age, and parity were associated with significantly higher risk of surgery. The significant univariate variables remained significant after multivariate analysis. ROC curve analysis revealed an excellent discrimination of the need for surgical treatment as predicted by TOA size, with increased likelihood of surgical or procedural intervention with increasing TOA size. CONCLUSION: Radiographic size, leukocyte count, age, and parity are associated with operative or procedural treatment of tuboovarian abscess.

A high-throughput small-molecule ligand screen targeted to agonists and antagonists of the G-protein-coupled receptor GPR54.

Recent data have shown that the G-protein-coupled receptor GPR54 (also known as KiSS-1 receptor) regulates GnRH release from the hypothalamus. This essential role of GPR54 in controlling the hypothalamic-pituitary-gonadal axis makes it an attractive target for therapeutic intervention in reproductive and cancer medicine. Currently, there are no small-molecule modulators of GPR54 function for experimental or clinical use. To identify small-molecule compounds that modify GPR54 signal transduction, the authors have adapted a cell-based functional assay for high-throughput screening (HTS) using a commercially available homogeneous time-resolved fluorescence assay for inositol phosphate accumulation. They generated stable Chinese hamster ovary cell transfectants that express human GPR54 for use in this assay. After optimization in an automated HTS environment, they screened a library of 110,000 small-molecule compounds using 2 protocols, one to identify agonists and one to identify antagonists. Hits obtained in the primary screen were confirmed to be active in secondary in vitro assays. Compounds identified as agonists or antagonists from HTS and secondary screening will be characterized to identify agents with the potential to be developed as novel orally active agents to treat hormone-dependent disorders such as abnormal puberty, infertility, endometriosis, and sex steroid-dependent tumors.

A GPR54-activating mutation in a patient with central precocious puberty.

Gonadotropin-dependent, or central, precocious puberty is caused by early maturation of the hypothalamic-pituitary-gonadal axis. In girls, this condition is most often idiopathic. Recently, a G protein-coupled receptor, GPR54, and its ligand, kisspeptin, were described as an excitatory neuroregulator system for the secretion of gonadotropin-releasing hormone (GnRH). In this study, we have identified an autosomal dominant GPR54 mutation--the substitution of proline for arginine at codon 386 (Arg386Pro)--in an adopted girl with idiopathic central precocious puberty (whose biologic family was not available for genetic studies). In vitro studies have shown that this mutation leads to prolonged activation of intracellular signaling pathways in response to kisspeptin. The Arg386Pro mutant appears to be associated with central precocious puberty.

Laparoscopic oophoropexy prior to radiation for pediatric brain tumor and subsequent ovarian function.

BACKGROUND: Ovarian failure has been reported to occur in female cancer survivors who had received spinal radiation as children. We aimed to determine whether laparoscopic unilateral oophoropexy prior to radiotherapy effectively preserves ovarian function. METHODS: In a retrospective analysis, the study group comprised girls, aged 18 and younger, who received spinal irradiation for a brain tumor. Ovarian dysfunction, the primary endpoint, was defined as an elevated follicle-stimulating hormone level or persistent amenorrhea. RESULTS: After applying exclusion criteria, 15 patients comprised the group that had undergone laparoscopic oophoropexy, and 11 patients comprised the comparison group that did not have oophoropexy. Mean age at diagnosis, length of follow-up, proportion of high-risk tumors and doses and duration of chemotherapy and radiation were not different between the two groups. Two of 15 patients (13%, 95% CI 0.2-40%) with oophoropexy had ovarian dysfunction compared with five of 11 (45%, 95% CI 17-77%) in the comparison group (P = 0.09). CONCLUSIONS: Oophoropexy may protect against radiation-induced ovarian failure in girls receiving spinal radiation. A high risk of ovarian dysfunction was seen in patients who did not undergo oophoropexy. In girls who underwent oophoropexy, a lower rate of ovarian dysfunction was seen.

Use of acellular human dermal allograft for vaginoplasty in Mayer-Rokitansky-Küster-Hauser syndrome: a case report.

BACKGROUND: Both autologous and synthetic tissue have been used to create a neovagina in women with Mayer-Rokitansky-Küster-Hauser syndrome. Despite reports on many different techniques, the ideal method of vaginoplasty has not been firmly established. CASE: A 33-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome had been unsuccessful in using vaginal dilators for the creation of a functional vagina with the Frank technique due to pain and vulvar lichen sclerosis. She thus elected to undergo vaginoplasty by a modified McIndoe procedure using acellular human dermal allograft material. Both the surgery and immediate postoperative course were uncomplicated. Vaginal apex stenosis resulted from inadequate dilatation in the weeks following surgery since the patient experienced pain with dilator use. CONCLUSION: The use of dermal allograft material instead of a split-thickness autologous skin graft is a simple and less invasive method of constructing a neovagina. Due to the many potential advantages of this technique, further investigation is warranted to optimize long-term outcomes of vaginoplasty using this method.

GPR54 and KiSS-1: role in the regulation of puberty and reproduction.

The finding of inactivating mutations in GPR54 in IHH patients and the lack of reproductive maturation of the GPR54 null mouse have uncovered a previously unrecognized role for GPR54 and KiSS-1 in the physiologic regulation of puberty and reproduction. This newly identified function for GPR54 and its cognate ligand, kisspeptin, has led to additional studies that have localized GPR54 and KiSS-1 mRNA in the hypothalamus, colocalized GPR54 in GnRH neurons, demonstrated GnRH-dependent activation of LH and FSH release by kisspeptin, and shown increased hypothalamic KiSS-1 and GPR54 mRNA levels at the time of puberty. Taken together, these findings establish the role of the kisspeptin-GPR54 system in the stimulation of GnRH neurons during puberty. The mechanisms by which kisspeptin activates GnRH release, as well as the trigger for this pathway at the onset of puberty, are yet to be elucidated. In the future, modulators of GPR54 activity, including kisspeptin, may prove valuable in clinical applications in the fields of both cancer therapy and reproductive medicine.

KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty.

The recent identification of loss-of-function mutations in the gene encoding GPR54, the receptor for the KiSS-1-derived peptides, kisspeptins, has highlighted a previously unrecognized pathway in the physiologic regulation of puberty and reproduction. Patients with loss-of-function mutations in GPR54 have idiopathic hypogonadotropic hypogonadism, and mice lacking GPR54 similarly fail to undergo puberty and have immature reproductive organs and low levels of sex steroids and gonadotropins. These observations have led to the hypothesis that kisspeptins activate hypothalamic GnRH release, thereby serving as a pivotal factor in the pubertal activation of the reproductive cascade. This hypothesis is supported by subsequent studies in rodent and primate models that have demonstrated localization of KiSS-1 mRNA in the hypothalamus, colocalization of GPR54 in GnRH neurons, GnRH-dependent activation of LH and FSH release by intracerebroventricular or peripheral administration of kisspeptin, and increased hypothalamic KiSS-1 and GPR54 mRNA levels at the onset of puberty. Taken together, these findings weave a compelling case for a role of the kisspeptin-GPR54 system in the activation of GnRH neurons at the time of pubertal awakening of the reproductive axis.

The GPR54 gene as a regulator of puberty.

BACKGROUND: Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. METHODS: We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein-coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. RESULTS: Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotropic hypogonadism was determined to have two separate mutations, R331X and X399R. The in vitro transfection of COS-7 cells with mutant constructs demonstrated a significantly decreased accumulation of inositol phosphate. The patient carrying the compound heterozygous mutations (R331X and X399R) had attenuated secretion of endogenous gonadotropin-releasing hormone and a left-shifted dose-response curve for gonadotropin-releasing hormone as compared with six patients who had idiopathic hypogonadotropic hypogonadism without GPR54 mutations. The Gpr54-deficient mice had isolated hypogonadotropic hypogonadism (small testes in male mice and a delay in vaginal opening and an absence of follicular maturation in female mice), but they showed responsiveness to both exogenous gonadotropins and gonadotropin-releasing hormone and had normal levels of gonadotropin-releasing hormone in the hypothalamus. CONCLUSIONS: Mutations in GPR54, a G protein-coupled receptor gene, cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans and mice, suggesting that this receptor is essential for normal gonadotropin-releasing hormone physiology and for puberty.

Characteristics of patients with endometriosis in the United States and the United Kingdom.

OBJECTIVE: To investigate differences in characteristics of patients with endometriosis in the United States and the United Kingdom. DESIGN: Patient questionnaire. SETTING: Two university-based endometriosis referral centers. PATIENT(S): Women with surgically diagnosed endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patient demographics, menstrual and obstetric history, contraceptive use, medical history, risk factors, family history, endometriosis diagnosis, and current pain status and treatment. RESULT(S): Most demographic characteristics were similar between groups. However, patients in the United States were diagnosed at a younger age than were patients in the United Kingdom (25.6 +/- 6.7 years vs. 28.0 +/- 7.1 years) and more commonly presented with an ovarian mass. More U.K. women used oral contraceptives before diagnosis and were younger at first use. U.K. patients underwent fewer additional surgeries than U.S. patients but reported that surgery alone provided the best relief of symptoms, whereas most U.S. patients reported that surgical and medical therapy together provided the best relief of symptoms. CONCLUSION(S): The many similarities in demographics and symptoms among women with endometriosis in the U.S. and the U.K. support the universality of the disease process. Despite a variety of treatments, most patients from both groups still experienced pain from their endometriosis at the time of the survey.