Hypoestrogenic Symptoms Research Articles

Perception and Comfort with Endometriosis Management Among OB/GYN Residents.

The diagnosis of endometriosis often takes several years, delaying appropriate care while patients suffer from pelvic pain, dysmenorrhea, and dyspareunia. Understanding whether residents in obstetrics and gynecology (OB/GYN) are being adequately exposed to and trained in the diagnosis and management of the disease is important for improving care. We conducted an online cross-sectional survey of OB/GYN residents to investigate their comfort level and familiarity with endometriosis diagnosis and management. Residency program directors and coordinators of 20 OB/GYN residency programs in California, USA were emailed to disseminate the 31-question, anonymous survey in January to February 2023. Responses were collected using Redcap and analysis was conducted using STATA. 67 residents answered at least one non-demographic question and were included. A resident response rate was not calculated because we were unable to determine how many programs distributed the survey. 84% of residents felt they could recognise symptoms of endometriosis but over 30% of senior residents were not comfortable with sonographic diagnosis of endometrioma. Approximately one third of residents felt comfortable managing hypoestrogenic symptoms, osteoporotic risks, and add-back progestin for certain hormonal therapies. Academic-hospital based residents had significantly more exposure to attendings prescribing long-acting reversible contraception, GnRH antagonists, and GnRH agonists but there were no significant differences in trainee prescribing practices or comfort. More respondents would feel comfortable medically managing endometriosis (52%) than surgically managing the disease (26%) if they were in practice today, with only 39% of PGY3-4 residents feeling comfortable surgically managing endometriosis. There is considerable room for improvement in the education of residents in the diagnosis and medical and surgical management of endometriosis.

Network analysis and experimental approach to investigate the potential therapeutic mechanism of zishen yutai pills on premature ovarian insufficiency

BackgroundAs society continues to develop, women are more at risk of gonadotoxic substance exposure. Consequently, the incidence of premature ovarian insufficiency (POI) has increased significantly in the past decades. Hormone replacement therapy (HRT) is recommended as the standard treatment to relieve hypoestrogenic symptoms; however, its potential side effects and contraindications have drawn widespread controversy and concern. As such, the Chinese medicine Zishen Yutai Pill (ZSYTP) commonly used for treating miscarriage and menoxenia, is a highly promising alternative drug candidate against POI, however its therapeutic mechanism has not been completely elucidated. ObjectiveTo systematically analyze the potential therapeutic targets of ZSYTP on POI, we combined network pharmacology analysis and molecular docking to predict critical target genes, with experimental validation on POI murine models. MethodsThe active compounds of ZSYTP were collected from three online databases, and the candidate targets were predicted based on the chemical structure. The POI-related targets were obtained from four databases. A PPI network was constructed to find the key target genes between ZSYTP and POI, while GO and KEGG enrichment analyses were employed to study the mechanism of ZSYTP against POI. The binding capability of the key co-targets with active components was examined by molecular docking. We used a cyclophosphamide (CTX)-inducible POI mouse model to verify our predictions by histopathological observation, immunohistochemical staining (caspase-3, TUNEL assay), hormone determination (FSH, AMH) and ribonucleic acid sequencing (RNA Seq). Progynova was also used to study the difference between ZSYTP and HRT. ResultWe identified 21 target genes as the hub between ZSYTP and POI. The GO and KEGG analyses revealed that the molecular mechanism of ZSYTP against POI were mainly based on the regulation of gene and protein expression. A variety of signaling pathways may be involved in the treatment of ZSYTP against POI, especially PI3K-AKT, HIF-1 and the AGE-RAGE cascades. Docking simulation showed that G1, C1, SR5, and F1 had relatively lower binding energy. In vivo, ZSYTP significantly reversed CTX-induced ovarian damage in follicle number, hormone level and apoptosis, with an overall improved therapeutic effect compared to Progynova. Results from RNA-Seq revealed that the PI3K-AKT, Hippo, AGE-RAGE, and Rap1 signaling pathways and regulation of inflammation, immune response, and lipid metabolism may mediate the protective effects of ZSYTP against POI, which is different than Progynova's mechanism of action. ConclusionsCollectively, this study indicates that ZSYTP could be a highly promising alternative as a non-HRT-based therapy for POI. Its mechanism involves multiple signaling pathways, alleviating ovarian apoptosis and recovering AMH and FSH level. However, the discrepancy between different research techniques highlight the necessity of further experimental verification from other aspects such as translation and posttranslational modification.

Health implications and management of early estrogen loss

The author discusses the health risks associated with early menopause and the benefits of hormone replacement therapy to mitigate these risks and alleviate hypoestrogenic symptoms as appropriate for individual patients.

Letrozole as premedication of high intensity focused ultrasound treatment of uterine fibroids: A retrospective observation study.

No reports on Letrozole as a pretreatment before ablation of uterine fibroid with high intensity focused ultrasound (HIFU), so a retrospective observation study was performed to evaluate the response of different pre-HIFU medication. We collected patients with single uterine fibroid receiving HIFU ablation from January 2018 to April 2021. All enrolled patients were classified into three group: group A (no pre-HIFU medication use), group B (Pre-HIFU letrozole use), group C (pre-HIFU gonadotrophin releasing hormone analog, GnRHa). Further associated clinical data and treatment response after HIFU treatment were reviewed and evaluated. A total of 39 patients including 21, 7, and 11 in group A, B, and C were collected respectively. After pre-HIFU medication, no difference of fibroid volume was found (A: 251.4, B: 360.6, C: 409.4 cm3, p = 0.250), and GnRHa group had significantly larger volume reduction than Letrozole users (38.6% vs. 16.4%, p = 0.007). The incidence of hypoestrogenic symptoms was higher in GnRHa group than in letrozole users (27.3% vs. 0, p = 0.170). GnRHa group had more sonication time (p = 0.001), treatment duration (p = 0.002), and ablated energy (p = 0.001) than group A and B. The treatment efficiency was higher in letrozole group than that in other 2 groups (4.52 vs. 2.39 vs. 2.34 cm3/min, p = 0.050). For patients with fibroid over 10 cm in diameter, letrozole group had even better energy efficiency (p = 0.067), treatment speed (p = 0.007), treatment efficiency (p = 0.001), NPV per energy (p = 0.005), and NPV per sonication (p = 0.004) than other 2 groups. Letrozole as a pretreatment medication before HIFU treatment might increase the energy efficiency and treatment efficiency of its ablation of uterine leiomyoma, especially for fibroid over 10 cm. Future study of larger patient number is needed to confirm our results.

Primary Ovarian Insufficiency: Time to Diagnosis and a Review of Current Literature

Background: Prompt recognition of symptoms and subsequent diagnosis of primary ovarian insufficiency (POI) are critical given its consequences on quality of life and long-term health. Poor access to care in underrepresented minority women and/or low-income populations may contribute to delayed diagnosis. Our group previously demonstrated a dearth of board-certified reproductive endocrinology (RE) physicians providing care for Medicaid patients in New Jersey. Given the adverse effects of prolonged hypoestrogenism, we aimed to evaluate length of time to diagnosis of POI in a low-resource/low-income population presenting to an urban university-based RE clinic, as well as provide a review of the current literature. Methods: This retrospective case series included all new patients seen at the RE clinic at University Hospital in Newark, NJ from June 2014 through June 2018. POI was diagnosed in women with oligo/amenorrhea and menopausal levels of follicle stimulating hormone. The primary outcome was time to diagnosis from onset of symptoms. Results: Of 524 new patients seen, 19 (3.6%) were diagnosed with POI. Median time to diagnosis of POI from onset of symptoms was 48 months. 57.9% of our patients identified as Black and 31.6% as Hispanic. 13/19 (68.4%) reported hypoestrogenic symptoms at time of referral. 21.1% were diagnosed with Turner mosaicism. 14 of 19 patients completed DEXA scan, of which 35.7% were diagnosed with low bone mass or osteoporosis. Of those diagnosed prior to referral to RE (9/19, 47.4%), only 4 had initiated hormone therapy. Conclusions: Our study demonstrates a need for more aggressive evaluation of oligo/amenorrhea in underrepresented minority women. Prolonged time to diagnosis of POI has adverse effects, as reflected by hypoestrogenic symptoms and decreased bone mineral density. Delayed diagnosis and management of POI may be related to health care disparities facing these women and warrants action to improve access to care.

Effect of hysterectomy on the function of saved ovaries and correction of hormonal imbalance

The objective: to assess the hormonal disorders in patients after the radical treatment for leiomyoma and to develop the therapeutic options for correction.Materials and methods. The clinical and laboratory assessment of postoperative course after leiomyoma surgery in 160 women of reproductive age was carried out. The following groups of patients were formed: I group – 90 patients after vaginal hysterectomy (HE) with opportunistic salpingectomy and ovarian preservation, II group – 70 patients after abdominal HE with opportunistic salpingectomy and ovarian preservation. The control group included 50 women of reproductive age with asymptomatic leiomyoma.Then the following groups were formed to assess the effectiveness of the proposed medical correction program: the main group – 46 patients after vaginal HE with fallopian tubes and 36 persons after abdominal HE with fallopian tubes – received the proposed medical correction program, and the comparison group – 44 and 34 individuals after vaginal and abdominal HE with opportunistic salpingectomy and ovarian preservation, respectively, with standard approach for postoperative and rehabilitative periods.The diagnostic program included the assessment of hormonal level, post-hysterectomy syndrome degree by modified menopausal index using survey, urogenital and sexual dysfunction, and the indicators of vulvovaginal atrophy according to the Barlow scale.Results. Neurovegetative symptoms were observed in 36,7 % patients in the I group and 48.6 % - II group, vegetative-vascular symptoms – 46.7 % and 62.3 %, respectively. Insomnia was characterized by the sleep process disorders, the preservation of the feeling of fatigue after waking up. It is necessary to mention that an increase in the proportion of cardiovascular diseases up to 36 months after surgery (hypertension, dyshormonal cardiomyopathy and their combinations, 23.1 % were diagnosed with dyshormonal mastopathy, the women complained on arthralgia, morning joint stiffness, ostealgia twice more.The assessment of sexual disorders and manifestations of urogenital tract dysfunction allowed to indicate the most significant rate of dysuria complains in 72.9 % of cases in the II group after classical abdominal HE. Up to 36 months after surgery the subclinical hypothyroidism was found in 62.2 % of women in the I group and 31.4 % – II group, clinically significant hypothyroidism – in 21.1 % and 55.7 %, respectively.In the half of the cases the hormonal imbalance like hypoesrogenia was determined up to 36 months of monitoring without statistically significant differences between groups of different HE methodic. The main factor was patient’s age in which endocrine, vegetative-vascular disorders and the clinical manifestations of psychosomatic are developed in a larger percentage of significantly earlier in women of late reproductive age.The use of proposed program of therapeutic options after HE with ovarian preservation allowed to provide a tendency of the estradiol, progesterone and testosterone levels normalization, prolactin and cortisol concentrations were close to the reference values. Estradiol concentration in the women in main group increased, although it remained significantly below the age normal indices, and the most significant normalization of theses parameters were determined in women who received hormonal replacement therapy. Clinically positive effect in patients on the severity of neurovegetative and psychoemotional manifestations on the background of differentiated treatment was observed after 3 months from the beginning of therapy.Conclusions. The obtained results suggest that the optimization of the treatment program with the the proposed drugs in women in the groups leads to relative optimization of hormonal status and initiation of compensatory-adaptive responses of the organism, which improves the quality of life and eliminates symptoms of hypoestrogenism.

Sexuality- and Fertility-Related Issues in Women after Allogeneic Hematopoietic Stem Cell Transplantation

Sexual dysfunction and fertility related issues appear as major post-allogeneic hematopoietic stem cell transplantation (HSCT) late effects in young women, with a heavy impact on quality of life. The objective of the present study was to evaluate the impact of disease and treatments on sexual quality of life, ovarian function, and family planning initiatives in the context of allogeneic HSCT. Between January 2014 and January 2016, adult female patientswho underwent HSCT before age 35 and had been followed formore than 2 years in our centerwere offered participation inthe study through a self-reported surveyand/or ovarian function assessment if age <40 at inclusion. A total of 63 patients were included, with a median age of 23.4 years at transplantation and 30.9 years at inclusion. Twenty-nine patients (46%) underwent HSCT for acute leukemia and 16 (25%) underwent HSCT for aplastic anemia (AA). The conditioning regimen was myeloablative conditioning (MAC) in 37 patients (59%) and reduced-intensity conditioning (RIC) in 26 (41%). Fifty-eight patients completed the survey, and 34 were evaluated for ovarian function. Symptoms of hypoestrogenism were reported by 86% of the patients and changes in sexual life were reported by 76%, due mainly to low sex drive, negative impact of infertility problems, physical sequelae, and loss of self-confidence. Premature ovarian failure (POF) occurred in 74% of patients and was significantly associated with conditioning regimen (MACversusRIC; P=.001) and baseline disease (bone marrow failureversusacute leukemiaversusothers; P < .001). However, one-half of the patients developed a POF despite the use of a RIC regimen. For 27 patients (47%), disease and treatments modified their desire for pregnancy, due mainly to fear of relapse and of disease transmission to offspring. Thirteen pregnancies were reported (21%), of which 8 were spontaneous and 5 were obtained through assisted reproductive technologies, mainly oocyte donation. With a median post-transplantation follow-up of 12.2 years, the 10-year cumulative incidence of first pregnancy was 16.6% (95% CI, 8.8-30.0). Among 20 patients (32%) who engaged in a family planning initiative, 13 (65%) succeeded in having children: 11 got pregnant and 2 adopted. Sixteen patients benefited from fertility preservation techniques consisting of ovarian tissue cryopreservation, and a single autologous ovarian tissue transplantation had been performed at the time of this report. This study shows a strong impact of disease and treatments on sexual quality of life, ovarian function, and family planning initiatives in the context of HSCT. It demonstrates the need to improve clinicians' awareness of sexual health- and fertility-related issues after HSCT. The difficulty of predicting ovarian function and fertility issues after RIC supports wide indications of pretransplantation fertility preservation. Evaluation of the use of cryopreserved ovarian tissues is warranted.

MiR-21 and Pellino-1 Expression Profiling in Autoimmune Premature Ovarian Insufficiency.

Background Premature ovarian insufficiency (POI) represents the hypergonadotropic hypoestrogenic symptoms that result in the loss of ovarian follicles. 5-30% POI cases are suggested to be involved in autoimmune etiology. MicroRNA-21 (miR-21) plays a vital role in ovarian folliculogenesis via regulating and interacting with multiple target genes. Here, we conduct the target prediction of miR-21, identify the expression and correlation of miR-21 and its putative target Pellino-1 (Peli1), and confirm their relationship with clinical characteristics in autoimmune POI. Methods Bioinformatic analysis was conducted to screen the miR-21 putative target gene. Autoimmune POI mouse models were established by ZP3 immunization. Serum miR-21, Peli1 mRNA of peripheral blood mononuclear cells (PBMCs) and regulatory T cells (Tregs), general status, spleen Tregs ratio, inflammatory factors, ovarian endocrine function, and ovarian structure were evaluated. For autoimmune POI patients, serum miR-21, PBMCs Peli1 mRNA levels, general data, immune parameters, hormone levels, and ultrasound examinations were obtained. The correlations of miR-21 with Peli1 and clinical characteristics in patients were analyzed. Results Peli1 was selected based on four microRNA prediction databases and literature retrieval. In mouse models, serum miR-21 level, PBMCs and Tregs Peli1 mRNA, and spleen Tregs ratio were 0.61 ± 0.09, 0.12 ± 0.12, 0.27±0.23 and 4.82 ± 0.58, respectively, lower than those in the control group. In patients, miR-21 level (0.60 ± 0.14) and Peli1 mRNA (0.30 ± 0.14) were lower than those in the control group (1.01 ± 0.07 and 1.63 ± 0.54); miR-21 was positively related with Peli1, AMH, E2, the size of the uterus, and ovarian volume and negatively related with FSH, LH, and the number of positive immune parameters (AOAb, EMAb, ACL, ANA, ds-DNA, ACA, IgG, IgA, IgM, IgE, C3, and C4). Conclusions Low expressions of miR-21 and Peli1 were detected in autoimmune POI mice and patients. Positive correlation between miR-21 and Peli1 was observed in autoimmune POI patients, suggesting that miR-21 and Peli1 might be associated with the pathogenesis of autoimmune POI.

Premature Ovarian Insufficiency: A Review

Premature ovarian insufficiency is waning of ovarian function before the age of 40 years. This hypoestrogenic state is characterised by menstrual irregularities and loss of fertility in the patient. This review narrates evaluation, consequences, and management of this complex entity. Truncation in ovarian physiology at such an early age renders the patient prone for various short- and long-term health consequences which negatively affect physical and psychological well-being of the patients. Therefore, this review emphasises that timely initiation of hormonal therapy is mandatory to mitigate the distressing menopausal and/or other hypoestrogenic symptoms to improve the quality of life of such patients. Although much has been said about premature ovarian insufficiency, many aspects of this condition still need to be explored in order to identify this population subgroup before happening of the catastrophic event and to formulate strategies and interventions to delay the premature cessation of ovarian functions.

Different Clinical Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS).

Complete androgen insensitivity syndrome (CAIS) is an X-linked recessive genetic disorder resulting from maternally inherited or de novo mutations involving the androgen receptor gene, situated in the Xq11-q12 region. The diagnosis is based on the presence of female external genitalia in a 46, XY human individual, with normally developed but undescended testes and complete unresponsiveness of target tissues to androgens. Subsequently, pelvic ultrasound or magnetic resonance imaging (MRI) could be helpful in confirming the absence of Mullerian structures, revealing the presence of a blind-ending vagina and identifying testes. CAIS management still represents a unique challenge throughout childhood and adolescence, particularly regarding timing of gonadectomy, type of hormonal therapy, and psychological concerns. Indeed this condition is associated with an increased risk of testicular germ cell tumour (TGCT), although TGCT results less frequently than in other disorders of sex development (DSD). Furthermore, the majority of detected tumoral lesions are non-invasive and with a low probability of progression into aggressive forms. Therefore, histological, epidemiological, and prognostic features of testicular cancer in CAIS allow postponing of the gonadectomy until after pubertal age in order to guarantee the initial spontaneous pubertal development and avoid the necessity of hormonal replacement therapy (HRT) induction. However, HRT is necessary after gonadectomy in order to prevent symptoms of hypoestrogenism and to maintain secondary sexual features. This article presents differential clinical presentations and management in patients with CAIS to emphasize the continued importance of standardizing the clinical and surgical approach to this disorder.

Elagolix sodium for the treatment of women with moderate to severe endometriosis-associated pain.

First-line medical therapies for treating pain associated with endometriosis mainly consist in combined oral contraceptives and progestins. However, some women, having persistence of symptoms, may require further therapeutic options. Among these, gonadotropin-releasing hormone (GnRH) agonists (GnRH-as) have been widely employed in the last 30 years, despite being characterized by an unfavorable safety profile. Currently, new alternative investigational options are being investigated to treat this benign chronic disease. GnRH antagonists (GnRH-ants) are innovative hormonal drugs that do not induce flare-up effects and present also a limited onset of hypoestrogenic symptoms; in fact, their pharmacological mechanism of action, which consists in pure antagonistic activity, differs from that of traditional GnRH-as. In July 2018, the U.S. Food and Drug Administration (FDA) approved elagolix sodium for the management of moderate to severe pain associated with endometriosis, after the drug showed promising efficacy and safety results in previous phase III trials. This monograph aims to provide a complete overview of the pharmacokinetics, clinical efficacy and safety of this GnRH-ant for treat¬ing patients with endometriosis.

Premature Ovarian Insufficiency: A Review

Premature ovarian insufficiency is waning of ovarian function before the age of 40 years. This hypoestrogenic state is characterised by menstrual irregularities and loss of fertility in the patient. This review narrates evaluation, consequences, and management of this complex entity. Truncation in ovarian physiology at such an early age renders the patient prone for various short- and long-term health consequences which negatively affect physical and psychological well-being of the patients. Therefore, this review emphasises that timely initiation of hormonal therapy is mandatory to mitigate the distressing menopausal and/or other hypoestrogenic symptoms to improve the quality of life of such patients. Although much has been said about premature ovarian insufficiency, many aspects of this condition still need to be explored in order to identify this population subgroup before happening of the catastrophic event and to formulate strategies and interventions to delay the premature cessation of ovarian functions.

Committee Opinion No. 698: Hormone Therapy in Primary Ovarian Insufficiency.

Primary ovarian insufficiency describes a spectrum of declining ovarian function and reduced fecundity due to a premature decrease in initial follicle number, an increase in follicle destruction, or poor follicular response to gonadotropins. The sequelae of primary ovarian insufficiency include vasomotor symptoms, urogenital atrophy, osteoporosis and fracture, cardiovascular disease, and increased all-cause mortality. In women with primary ovarian insufficiency, systemic hormone therapy (HT) is an effective approach to treat the symptoms of hypoestrogenism and mitigate long-term health risks if there are no contraindications to treatment. Hormone therapy is indicated to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy and to improve the quality of life of women with primary ovarian insufficiency. Although exogenous estrogen replacement is recommended for women with primary ovarian insufficiency, data comparing various hormonal regimens for disease prevention, symptom amelioration, and safety are lacking in this population. As a first-line approach, HT (either orally or transdermally) that achieves replacement levels of estrogen is recommended. Combined hormonal contraceptives prevent ovulation and pregnancy more reliably than HT; despite only modest odds of spontaneous pregnancy in women with primary ovarian insufficiency, this is a critical consideration for those who deem pregnancy prevention a priority. Treatment for all women with primary ovarian insufficiency should continue until the average age of natural menopause is reached (age 50-51 years). Finally, considering the challenges that adolescents and young women may face in coping with the physical, reproductive, and social effects of primary ovarian insufficiency, comprehensive longitudinal management of this condition is essential.

Committee Opinion No. 698 Summary: Hormone Therapy in Primary Ovarian Insufficiency

Primary ovarian insufficiency describes a spectrum of declining ovarian function and reduced fecundity due to a premature decrease in initial follicle number, an increase in follicle destruction, or poor follicular response to gonadotropins. The sequelae of primary ovarian insufficiency include vasomotor symptoms, urogenital atrophy, osteoporosis and fracture, cardiovascular disease, and increased all-cause mortality. In women with primary ovarian insufficiency, systemic hormone therapy (HT) is an effective approach to treat the symptoms of hypoestrogenism and mitigate long-term health risks if there are no contraindications to treatment. Hormone therapy is indicated to reduce the risk of osteoporosis, cardiovascular disease, and urogenital atrophy and to improve the quality of life of women with primary ovarian insufficiency. Although exogenous estrogen replacement is recommended for women with primary ovarian insufficiency, data comparing various hormonal regimens for disease prevention, symptom amelioration, and safety are lacking in this population. As a first-line approach, HT (either orally or transdermally) that achieves replacement levels of estrogen is recommended. Combined hormonal contraceptives prevent ovulation and pregnancy more reliably than HT; despite only modest odds of spontaneous pregnancy in women with primary ovarian insufficiency, this is a critical consideration for those who deem pregnancy prevention a priority. Treatment for all women with primary ovarian insufficiency should continue until the average age of natural menopause is reached (age 50-51 years). Finally, considering the challenges that adolescents and young women may face in coping with the physical, reproductive, and social effects of primary ovarian insufficiency, comprehensive longitudinal management of this condition is essential.

Analysis of Adherence, Persistence, and Surgery Among Endometriosis Patients Treated with Leuprolide Acetate Plus Norethindrone Acetate Add-Back Therapy.

Endometriosis affects over 10 million women in the United States. Depot leuprolide acetate (LA), a gonadotropin-releasing hormone agonist, has been used extensively for the treatment of women with endometriosis but is associated with hypoestrogenic symptoms and bone mineral density loss. The concomitant use of add-back therapies, specifically norethindrone acetate (NETA), can alleviate these adverse effects. To compare adherence to and persistence with LA treatment and time to endometriosis-related surgery among women treated with NETA and women treated with LA plus other add-back therapies or LA only. This retrospective analysis was conducted using Truven Health MarketScan Commercial Claims and Encounters Database. Women with a diagnosis of endometriosis (ICD-9-CM code 617.xx) who initiated LA (index date) in 2005-2011 were selected for inclusion. Additional requirements were 12 months of continuous enrollment pre- and post-index and no evidence of endometriosis-related surgeries pre-index or up to 30 days post-index; no pre-index use of estrogen or noncontraceptive hormones; and no diagnoses of uterine fibroids, malignant neoplasms, infertility, or pregnancy. Patients were characterized as using NETA; other add-back therapies (estrogens, progestins, or estrogen-progestin combinations); or no add-back therapy. Adherence to and persistence with LA were measured over the 6 months following the index date using outpatient medical and pharmacy claims. Patients were considered adherent if their proportion of days covered was greater than or equal to 0.80. Persistence was operationalized as time to discontinuation, defined as a continuous gap of > 60 days without LA on hand. Time to endometriosis-related surgery (laparotomy, laparoscopy, excision/ablation/fulguration, oophorectomy, and hysterectomy) was measured over the 12 months following the index date. Surgeries were identified from inpatient and outpatient medical claims using procedure codes. Outcomes were compared among cohorts using multivariable logistic and Cox proportional hazards regression models controlling for demographics and baseline clinical characteristics. The final sample included 3,114 women, with a mean age of 36.9 years. The majority of women used LA only with no add-back therapy (n = 1,963, 63.0%), while 15.1% (n = 470) used NETA, and 21.9% (N = 681) used other add-back therapies. During the 6-month follow-up, more patients in the LA plus NETA cohort were adherent to LA therapy compared with LA only (47.2% vs. 31.5%, P < 0.001), and fewer patients discontinued (37.9% vs. 59.6%, P < 0.001). Additionally, fewer patients underwent endometriosis-related surgery in the 12 months after LA initiation in the LA plus NETA cohort (12.6% vs. 16.9%, P = 0.021). In multivariable models, women who initiated LA plus NETA or LA plus other add-back therapies had a higher likelihood of being adherent to LA than LA only patients (OR = 1.91, 95% CI = 1.55-2.36 and OR = 1.95, 95% CI = 1.63-2.34) and lower likelihood of LA discontinuation (HR = 0.54, 95% CI = 0.46-0.63 and HR = 0.59, 95% CI = 0.52-0.68). NETA patients had a lower surgery rate in the 12-month post-index period compared with other add-back patients (HR = 0.68, 95% CI = 0.50-0.93) or LA only patients (HR = 0.69, 95% CI = 0.52-0.92). For women with endometriosis, treatment with LA and concomitant add-back therapies was associated with better adherence to and persistence with LA over the 6 months following initiation, compared with treatment with LA only. The increased adherence and persistence to LA may translate into decreased need for surgical intervention, although fewer endometriosis-related surgeries were only observed in the 12 months following LA initiation for patients using concomitant NETA add-back therapy. These results support an increased and earlier use of NETA add-back therapy among women who initiate LA. This study was funded by AbbVie, which also markets the endometriosis drugs Lupron and Lupaneta Pack. AbbVie participated in the study design, research, data collection, analysis and interpretation, writing, review, and approval of this publication. Soliman and Castelli-Haley are employees of AbbVie and may own AbbVie stock or stock options. Bonafede and Farr are employees of Truven Health Analytics, which received a research contract to conduct this study with and on behalf of AbbVie. Winkel is a clinical professor in the Department of Obstetrics and Gynecology at Georgetown University in Washington, DC, and has served in a consulting role on research to AbbVie for this project. An earlier version of the current research was presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 20th Annual International Meeting; Philadelphia, PA; May 2015. All authors participated in data analysis and interpretation and contributed to the development of the manuscript.

Effects of different add-back regimens on hypoestrogenic problems by postoperative gonadotropin-releasing hormone agonist treatment in endometriosis.

ObjectiveTo compare the efficacy of different add-back regimens on hypoestrogenic symptoms during postoperative gonadotropin-releasing hormone (GnRH) agonist treatment in endometriosis patients.MethodsThis prospective cohort study included reproductive-aged women who underwent conservative laparoscopic surgery for ovarian endometriosis and received add-back therapy during a 6-month course of GnRH agonist therapy after surgery. Participants received one of four different add-back regimens: 1 mg of estradiol valerate, 2.5 mg of tibolone, or a combination of 1 mg of estradiol and 2 mg of drospirenone or 0.5 mg of norethisterone acetate. Changes in quality of life, hypoestrogenic symptoms, and bone mineral density were compared according to add-back regimens.ResultsA total of 57 participants completed a 6-month course of GnRH agonist and add-back therapy. All components of quality of life did not differ across groups. However, within the same treatment group, social relationship factors decreased significantly with estradiol valerate and tibolone alone, and environmental factors decreased significantly with estradiol valerate alone. Menopausal Rating Scale score did not change significantly, but the incidence of hot flushes significantly decreased with a combination of estradiol and norethisterone acetate. Bone mineral densities at the lumbar spine declined significantly after treatment in all groups except with a combination of estradiol and norethisterone acetate.ConclusionThis preliminary study suggests that an add-back regimen containing estradiol valerate and norethisterone acetate may have better efficacy in terms of quality of life, hypoestrogenism-associated symptoms, and bone mineral density.

Application of the estrogen threshold hypothesis to the physiologic hypoestrogenemia of lactation.

This study determined the impact of breastfeeding on hypoestrogenic symptoms among women in the postpartum period and correlated these findings with the Estrogen Threshold Hypothesis, which postulates that the hypoestrogenic symptoms experienced are related to circulating estrogen levels. Using a survey instrument that combined previously validated assessments of postpartum mood changes and menopausal symptoms, women were evaluated in the immediate postpartum period, prior to hospital discharge, and at 3 and 6 weeks postpartum. Each time period was analyzed independently, in a cross-sectional design, where women were categorized as "breastfeeding" or "bottle feeding." Of 236 women recruited, 171 (72.5%) intended to breastfeed, and 62 (26.3%) intended to bottle feed. At both the 3- and 6-week postpartum evaluations, a similar percentage of women in the breastfeeding and bottle-feeding groups reported hot flashes. However, breastfeeding women were more likely to report vaginal dryness than those who did not breastfeed: 20/150 (13.3%) versus 3/80 (3.8%) at 3 weeks, p<0.05; 25/143 (17.5%) versus 2/87 (2.3%) at 6 weeks, p<0.001. The Estrogen Threshold Hypothesis accurately predicts the findings of increased reported vaginal dryness but not hot flashes during lactation.

Treatment of Endometriosis with the GnRHa Deslorelin and Add-Back Estradiol and Supplementary Testosterone.

Background. This randomized, multicenter, open-label clinical trial was intended to generate pilot data on the efficacy and safety of the gonadotropin-releasing hormone agonist (GnRHa) deslorelin (D) with low-dose estradiol ± testosterone (E2 ± T) add-back for endometriosis-related pelvic pain. Methods. Women with pelvic pain and laparoscopically confirmed endometriosis were treated with a six-month course of daily intranasal D with concurrent administration of either transdermal E2, intranasal E2, or intranasal E2 + T. Efficacy data included evaluation of dyspareunia, dysmenorrhea, pelvic pain, tenderness, and induration. Cognition and quality of life were also assessed. Safety parameters included assessment of endometrial hyperplasia, bone mineral density (BMD), and hot flashes. Results. Endometriosis symptoms and signs scores decreased in all treatment arms from a baseline average of 7.4 to 2.5 after 3 months of treatment and 3.4 after 6 months. BMD changes and incidence of hot flashes were minimal, and no endometrial hyperplasia was observed. Patient-reported outcomes showed significant improvement across multiple domains. Conclusions. Daily intranasal D with low dose E2 ± T add-back resulted in significant reduction in severity of endometriosis symptoms and signs with few safety signals and minimal hypoestrogenic symptoms that would be expected with the use of a GnRHa alone.

Spanish consensus on premature menopause

IntroductionWhile we recognise that the term premature menopause is more accepted by most non-specialist health care providers and by the general population, ‘primary ovarian insufficiency’ (POI) is currently considered the most apposite term to explain the loss of ovarian function, because it better explains the variability of the clinical picture, does not specify definitive failure, and highlights the specific ovarian source. Its pathogenesis involves a congenital reduction in the number of primordial follicles, poor follicle recruitment, or accelerated follicular apoptosis. However, its cause is unknown in most cases. AimThis guide analyses the factors associated with the diagnosis and treatment of POI and provides recommendations on the most appropriate diagnostic and therapeutic measures for women under 40 years of age who experience POI. MethodologyA panel of experts from various Spanish scientific societies related to POI (Spanish Menopause Society, Spanish Fertility Society, and Spanish Contraception Society) met to reach a consensus on these issues. ResultsHormonal therapy (HT) is considered the treatment of choice to alleviate the symptoms of hypoestrogenism and to prevent long-term consequences. We suggest that HT should be continued until at least age 51, the average age at natural menopause. The best treatment to achieve pregnancy is oocyte/embryo donation. If a patient is to undergo treatment that will reduce her fertility, she should be informed of this issue and the available techniques to preserve ovarian function, mainly vitrification of oocytes.

Management of hypogonadism in adolescent girls and adult women with Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3 ± 7.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting-center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20 ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual-specific treatment; contraceptive pills, intra-uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26-year-old woman with inhibin B and FSH levels 53 ng/ml and 6.4 IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult.