ACR Appropriateness Criteria® Management of Uterine Fibroids: 2023 Update.

Uterine fibroids are the most common benign tumor in women of reproductive age and can present with symptoms including bleeding, bulk related symptoms, and infertility. Several treatment options are available for the management of uterine fibroids, including medical management, minimally invasive therapies such as uterine artery embolization and MR-guided focused ultrasound ablation, and surgical interventions ranging from laparoscopic myomectomy to open hysterectomy. Given this wide range of therapeutic interventions, it is important to understand the data supporting these interventions and to be able to apply it in different clinical settings. This document provides a summary of recent trials supporting various therapies for uterine fibroids, including recent evidence for MR-guided focused ultrasound ablation and a detailed discussion of fertility outcomes in myomectomy and uterine fibroid embolization. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

A combination of laparoscopy and bilateral uterine artery occlusion for the treatment of type II cesarean scar pregnancy: a retrospective analysis.

OBJECTIVE: We investigated the efficacy of a combination of laparoscopy and bilateral uterine artery occlusion (BUAO) for the treatment of type II cesarean scar pregnancy (CSP). METHODS: Patients with type II CSP underwent laparoscopy + bilateral uterine artery embolization (control group) or laparoscopy + BUAO (study group). Data regarding the duration of surgery, intraoperative hemorrhage, postoperative complications, the duration of the hospital stay, and the costs of hospitalization were retrospectively collected. One year later, the time to the return of the ß-human chorionic gonadotropin (ß-hCG) concentration to normal and to the return of menstruation were compared. RESULTS: The duration of surgery, time to the return of menstruation, and incidence of postoperative complications in the study group were significantly less than in the control group, but there was no significant difference in the time for ß-hCG to return to normal or the volume of intraoperative hemorrhage. The duration of hospitalization and costs for the control group were higher than those for the study group. CONCLUSION: Laparoscopy in combination with BUAO is associated with minimal trauma, rapid recovery, a short duration of surgery, low cost of hospitalization, and a low postoperative complication rate. Thus, it represents a useful new surgical treatment for type II CSP.

Clinical outcomes and future fertility after uterine artery embolization for postpartum and post-abortion hemorrhage.

BACKGROUND: Postpartum hemorrhage (PPH) and post-abortion hemorrhage (PAH) are life-threatening conditions. PURPOSE: To evaluate the efficacy and safety of uterine arterial embolization (UAE) for PPH and PAH and to investigate future fertility after UAE. MATERIAL AND METHODS: This study included 57 consecutive patients (mean age = 34 years) who underwent UAE for PPH (n = 46) and PAH (n = 11) at our institution between January 2011 and December 2022. Technical success, non-visualization of the peripheral portion of bilateral uterine arteries on angiography, and clinical success, complete hemostasis after UAE, were assessed. UAE-associated complications and factors related to clinical success were analyzed. Pregnancy outcomes after UAE and complications during subsequent pregnancy were investigated in 16 patients who desired fertility and were followed up for >1 year. RESULTS: The technical and clinical success rates were 100% and 84.2%, respectively. Sepsis (n = 1) and uterine empyema (n = 1) were observed as severe complications. Placental disorder, bleeding within 24 h after delivery or abortion, ≥1.5 shock index, ≥6 units of transfusion erythrocytes, and ≥8 obstetrical disseminated intravascular coagulation score were significantly associated with unfavorable clinical outcomes. In total, 16 pregnancies were observed in 12 patients after UAE, three of which were miscarriages and 13 were successful live births. During pregnancy, uterine rupture (n = 1) and accreta (n = 1) were observed. CONCLUSION: UAE is an effective treatment for PPH and PAH. Although UAE could preserve future fertility, careful attention should be paid to perinatal management for unusual complications.

Pantoea agglomerans bacteraemia after uterine artery embolisation: an unusual pathogen.

A woman in her 40s presented to the emergency department (ED) with a 3-week history of nausea, vomiting and diarrhoea. Blood cultures were positive for Serratia and Pantoea agglomerans spp. One month before her ED visit, she underwent targeted uterine artery embolisation with particles by an interventional radiologist. Uterine artery embolisation is considered a safe alternative to surgical removal of fibroids or hysterectomy. The patient was initially treated with targeted antibiotics for a large infected uterine fibroid but ultimately required a hysterectomy for source control. To our knowledge, this is the first documented case of P. agglomerans infecting a uterine fibroid.

Management of placenta accreta spectrum in low- and middle-income countries.

Placenta accreta spectrum (PAS) can be associated massive intra- and post-operative hemorrhage which when not controlled can lead to maternal death. Important advances have occurred in understanding the pathophysiology and therapeutic options for this condition. The prevalence of PAS at birth is direct association with the cesarean delivery (CD) rate in the corresponding population and is increasing worldwide. Limited health infrastructure in low- and middle-income countries increases the morbidity and mortality of patients with PAS at birth. In many cases, obstetricians working in limited resources settings cannot follow some of the international guideline's recommendations and have to opt for low-cost management procedures. In this review, we describe the particularities of managing PAS care in low- and middle-income countries from of prenatal evaluation of patients at risk of PAS at birth, therapeutic options, and inter-institutional collaboration. We also propose a management protocol based on training of the local obstetric teams rather than on sophisticated technological resources that are almost never available in low-resource scenarios.

Dilatation and Curettage after Uterine Artery Embolization versus Methotrexate Injection for the Treatment of Cesarean Scar Pregnancy: A Single-Center Experience.

Background and Objectives: Cesarean scar pregnancy (CSP) represents a type of ectopic pregnancy in which the embryo implants inside the scar of a previous cesarean section. This condition can lead to maternal morbidity and mortality. The best therapeutic approach in terms of clinical effectiveness and patient safety for CSP has not been described yet, although different therapeutic strategies are currently available. The purpose of the present study was to analyze the success rate of two different treatments in a single institution. Materials and Methods: A retrospective study was performed among patients diagnosed with CSP at the Gynecology and Obstetrics Department of the "Cannizzaro" Hospital in Catania (University of Enna-Italy) from January 2016 to December 2022. The diagnosis was made by 2D/3D transvaginal ultrasound, following Timor-Tritsch criteria. Two treatment strategies were performed: local and systemic methotrexate (MTX) injection and uterine artery embolization (UAE) with subsequent dilatation and curettage (D&C). All treated women underwent subsequent clinical and sonographic follow-up. Complete recovery was defined as the reduction of ß-HCG values until it was undetectable and the disappearance of the mass in the uterine scar on ultrasound. Results: Nineteen patients were included; nine were in the MTX group and ten were in the UAE + D&C group. No significant differences were found between the two groups in terms of clinical parameters. Treatment was successful in 4 of 10 (44%) patients in the MTX group and 10 of 10 (100%) in the UAE + D&C group (p = 0.01); the length of hospital stay was significantly shorter in the latter group (p < 0.0001). Conclusions: In our experience, administration of MTX is not recommended as the primary treatment or pre-treatment. Dilatation and curettage after uterine artery embolization are better than methotrexate injection for the treatment of cesarean scar pregnancy in a single-institution series in terms of complete recovery and length of hospital stay.

Surgical evacuation combined with Shirodkar cervical suture and selective uterine artery embolization: A fertility preserving treatment for 10-15 weeks' live cesarean scar ectopic pregnancies.

INTRODUCTION: Cesarean scar ectopic pregnancies (CSEPs) are associated with significant maternal morbidity and termination is often recommended in the early first trimester. Management of more advanced cases is challenging due to higher risks of major intraoperative hemorrhage. Hysterectomy is currently the intervention of choice for advanced cases. This study aimed to investigate if advanced live CSEPs could be managed effectively conservatively using suction curettage and interventional radiology. MATERIAL AND METHODS: A retrospective single-center cohort study was performed. A total of 371 women diagnosed with CSEP were identified between January 2008 and January 2023. A total of 6% (22/371) women had an advanced live CSEP with crown-rump length (CRL) of ≥40 mm (≥10 weeks' gestation). Of these, 77% (17/22) opted for surgical intervention, whilst the remaining five continued their pregnancies. A preoperative ultrasound was performed in each patient. All women underwent suction curettage under ultrasound guidance and insertion of Shirodkar cervical suture as a primary hemostatic measure combined with uterine artery embolization (UAE) if required. The primary outcome was rate of blood transfusion. Secondary outcomes were estimated intraoperative blood loss, UAE, intensive care unit admission, reintervention, hysterectomy, hospitalization duration and rate of retained products of conception. Descriptive statistics were used to describe these variables. RESULTS: Median CRL of the 17 patients included was 54.1 mm (range: 40.0-85.7) and median gestational age based on CRL was 12 + 3 weeks (range: 10 + 6-15 + 0). On preoperative ultrasound scan placental lacunae were recorded in 76% (13/17) of patients and color Doppler score was ≥3 in 67% (10/15) of patients. At surgery, Shirodkar cervical suture was used in all cases. It was successful in achieving hemostasis by tamponade in 76% (13/17) of patients. In the remaining 24% (4/17) patients tamponade failed to achieve complete hemostasis and UAE was performed to stop persistent arterial bleeding into the uterine cavity. Median intraoperative blood loss was 800 mL (range: 250-2500) and 41% (7/17) women lost >1000 mL. 35% (6/17) needed blood transfusion. No women required hysterectomy. CONCLUSIONS: Surgical evacuation with Shirodkar cervical suture and selective UAE is an effective treatment for advanced live CSEPs.

Application of Uterine Artery Embolization in Patients With Placenta Accreta Spectrum After Abdominal Aortic Balloon Occlusion.

OBJECTIVE: To evaluate the application of different uterine artery embolization procedures under balloon occlusion of the abdominal aorta in patients with Placenta Accreta Spectrum (PAS) undergoing cesarean section. MATERIALS AND METHODS: A retrospective analysis was performed on clinical data from 72 patients who underwent uterine artery embolization for hemostasis during cesarean section with PAS. The patients were divided into two groups according to the embolization method used during surgery: group A (n = 43) underwent uterine artery embolization by withdrawing the balloon and inserting a Cobra catheter into the uterine artery for embolization, while group B (n = 29) underwent uterine artery embolization with a Cobra catheter inserted via contralateral puncture of the femoral artery and balloon occlusion. General information, surgical data, and postoperative recovery were compared between the 2 groups. RESULTS: The bleeding and transfusion volumes were lower in group B than in group A and the differences between the 2 groups were statistically significant. There were no significant differences in surgical duration, number of embolized vessels, length of hospital stay, postoperative complications, or menstrual recovery between the 2 groups. CONCLUSION: For patients with PAS undergoing cesarean section, uterine artery embolization for hemostasis is preferably performed by inserting a Cobra catheter via contralateral puncture of the femoral artery under abdominal aortic balloon occlusion.

Patient Characteristics Associated With Embolization Versus Hysterectomy for Uterine Fibroids: A Systematic Review and Meta-Analysis.

INTRODUCTION: Black and underinsured women in the United States are more likely than their counterparts to develop uterine fibroids (UFs) and experience more severe symptoms. Uterine artery embolization (UAE), a uterine-sparing therapeutic procedure, is less invasive than the common alternative, open hysterectomy. To determine whether demographic disparities persist in UF treatment utilization, we reviewed patient characteristics associated with UAE versus hysterectomy for UF among studies of US clinical practices. METHODS: A systematic literature review was conducted via PubMed, Embase, and CINAHL (PROSPERO CRD42023455051), yielding 1,350 articles (January 1, 1995, to July 15, 2023) that outlined demographic characteristics of UAE compared with hysterectomy. Two readers screened for inclusion criteria, yielding 13 full-text US-based comparative studies specifying at least one common demographic characteristic. Random effects meta-analysis was performed on the data (STATA v18.0). Egger's regression test was used to quantify publication bias. RESULTS: Nine (138,960 patients), four (183,643 patients), and seven (312,270 patients) studies were analyzed for race, insurance status, and age as predictors of treatment modality, respectively. Black race (odds ratio = 3.35, P < .01) and young age (P < .05) were associated with UAE, whereas private insurance (relative to Medicare and/or Medicaid) was not (odds ratio = 1.06, P = .52). Between-study heterogeneity (I2 > 50%) was detected in all three meta-analyses. Small-study bias was detected for age but not race or insurance. CONCLUSIONS AND IMPLICATIONS: Knowledge of demographic characteristics of patients with UFs receiving UAE versus hysterectomy is sparse (n = 13 studies). Among these studies, which seem to be racially well distributed, Black and younger women are more likely to receive UAE than their counterparts.

True Costs of Uterine Artery Embolization: Time-Driven Activity-Based Costing in Interventional Radiology Over a 3-Year Period.

PURPOSE: The aim of this study is to uncover potential areas for cost savings in uterine artery embolization (UAE) using time-driven activity-based costing, the most accurate costing methodology for direct health care system costs. METHODS: One hundred twenty-three patients who underwent outpatient UAE for fibroids or adenomyosis between January 2020 and December 2022 were retrospectively reviewed. Utilization times were captured from electronic health record time stamps and staff interviews using validated techniques. Capacity cost rates were estimated using institutional data and manufacturer proxy prices. Costs were calculated using time-driven activity-based costing for personnel, equipment, and consumables. Differences in time utilization and costs between procedures by an interventional radiology attending physician only versus an interventional radiology attending physician and trainee were additionally performed. RESULTS: The mean total cost of UAE was $4,267 ± $1,770, the greatest contributor being consumables (51%; $2,162 ± $811), followed by personnel (33%; $1,388 ± $340) and equipment (7%; $309 ± $96). Embolic agents accounted for the greatest proportion of consumable costs, accounting for 51% ($1,273 ± $789), followed by vascular devices (15%; $630 ± $143). The cost of embolic agents was highly variable, driven mainly by the number of vials (range 1-19) of tris-acryl gelatin particles used. Interventional radiology attending physician only cases had significantly lower personnel costs ($1,091 versus $1,425, P = .007) and equipment costs ($268 versus $317, P = .007) compared with interventional radiology attending physician and trainee cases, although there was no significant difference in mean overall costs ($3,640 versus $4,386; P = .061). CONCLUSIONS: Consumables accounted for the majority of total cost of UAE, driven by the cost of embolic agents and vascular devices.

Comparing magnetic resonance imaging and ultrasound in the clinical evaluation of fibroids prior to uterine artery embolization.

PURPOSE: Uterine artery embolization has become established as a frontline treatment for uterine leiomyomata. In planning embolization, preprocedural imaging can further characterize pathology and anatomy, but it may also reveal coexisting diagnoses that have the potential to change clinical management. The purpose of this study is to compare the diagnostic outcomes of ultrasound and MRI performed for patients prior to undergoing embolization. METHODS: The study cohort consisted of 199 patients who underwent uterine artery embolization at a single academic institution between 2013 and 2018. Prior to embolization, all patients had an MRI confirming a leiomyomata diagnosis. Additionally, 118 patients underwent transvaginal ultrasound within five years prior to MRI. MRI findings were analyzed and, when applicable, compared to prior ultrasound impressions to assess for the incidence of new findings. The diagnoses of interest were adenomyosis, hydrosalpinx, predominantly infarcted leiomyomata, and large intracavitary leiomyomata. Data were collected from retrospective chart review and included demographics, symptomology, and imaging reports. RESULTS: 199 patients ultimately underwent embolization for treatment of MRI-confirmed leiomyomata. Of 118 patients who also had an ultrasound within five years prior to their MRI, 26 (22.0%) received a second gynecologic diagnosis based on MRI findings that was not previously seen on ultrasound. Of 81 patients who only had an MRI before embolization, 19 (23.5%) received a second gynecologic diagnosis not previously documented. The most common coexisting pathology was adenomyosis, presenting in 34 (17.1%) patients with leiomyomata, followed by large intracavitary leiomyomata (8, 4.0%), infarcted leiomyomata (7, 3.5%), and hydrosalpinx (6, 3.0%),. CONCLUSIONS: When considering uterine artery embolization for the treatment of symptomatic leiomyomata, preprocedural MRI is superior to ultrasound in detecting coexisting pathologies, including adenomyosis and hydrosalpinx. It can also better characterize leiomyomata, including identifying lesions as intracavitary or infarcted. These findings have the potential to alter clinical management or contraindicate embolization entirely.

Clinical efficacy and risk factors for suction curettage and hysteroscopy in patients with type I and II cesarean scar pregnancy.

OBJECTIVE: To investigate the clinical efficacy and evaluate risk factors for suction curettage (SC) and hysteroscopy in the treatment of type I and II cesarean scar pregnancy (CSP). METHODS: This was a retrospective study including 100 women diagnosed with type I/II CSP. Patients were treated with either ultrasound-guided SC (SC group) or hysteroscopy resection (surgery group). The success rates, mean operation time, hospitalization duration, hospitalization cost, risk factors, adverse events, and complications were analyzed. RESULTS: The success rate of the SC and surgery groups were 85% and 100%, respectively, and the difference was statistically significant (P = 0.032). There was one case of type I CSP and eight cases of type II CSP that failed SC treatment. No failed cases were found in the surgery group. Analysis of the causes of treatment failure revealed that diameter of the gestational sac was a risk factor for SC failure (odds ratio, 19.66 [95% confidence interval {CI}, 1.70-227.72], P = 0.017). Comparing the clinical outcomes between the SC and surgery groups, although the mean operation time of the SC group was significantly shorter than the surgery group (15 [CI, 15-20] vs. 30 [CI, 27-40], P = 0.001), the cost and duration of hospitalization were significantly lower in the surgery group than that in the SC group. No significant differences were observed for adverse events and complications between the two groups (P > 0.05). CONCLUSION: Hysteroscopy is an effective and economical method for treating type I/II CSP. Moreover, SC is not recommended for patients with type I/II CSP with a gestation age ≥8 weeks.

Efficacy of intra-arterial lidocaine administration on pain and inflammatory response after uterine artery embolization for symptomatic fibroids.

BACKGROUND: There have been conflicting outcomes regarding the use of lidocaine to reduce pain after uterine artery embolization (UAE). PURPOSE: To investigate the efficacy of intra-arterial lidocaine injection for pain and inflammatory response control within 24 h of UAE for symptomatic uterine fibroids. MATERIAL AND METHODS: Of 1530 patients who underwent UAE for uterine fibroids in 2007-2021, 5 mL of 1% lidocaine was injected into each uterine artery immediately after UAE in 23 patients. A disease-matched control group (n = 23) who did not receive intra-arterial lidocaine was generated from the same registry. The pain score, white blood cell (WBC) count, C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), and fentanyl consumption were compared before and after UAE. Complete infarction of the dominant fibroid was assessed using magnetic resonance imaging. RESULTS: Significantly lower WBC count, CRP level, and NLR were noted 24 h after UAE in the lidocaine group. No statistically significant difference was noted in the pain score between groups at 0-24 h. The cumulative fentanyl dose administered during the first 24 h after UAE was not significantly different. After embolization, fibroid-related symptoms resolved in all patients. No significant difference was observed in the rate of complete infarction of the dominant fibroid. CONCLUSION: Lidocaine administration immediately after UAE resulted in a significant reduction in the inflammatory response. However, such a difference in the inflammatory reaction did not contribute to significant reductions in pain scores or fentanyl consumption.

Treatment of adenomyosis, abdominal wall endometriosis and uterine leiomyoma with interventional radiology: A review of current evidences.

Interventional radiology shows promises in the field of women's health, particularly in pelvic interventions. This review article discusses the latest advancements in interventional radiology techniques for pelvic conditions affecting women including adenomyosis, abdominal wall endometriosis and uterine leiomyoma. Extraperitoneal endometriosis involving the abdominal wall may be treated by percutaneous thermal ablation, such as cryoablation, whereas uterine leiomyoma and adenomyosis can be managed either using percutaneous thermal ablation or using uterine artery embolization. Continued research and development in interventional radiology will further enhance the minimally-invasive interventions available for women's health, improving outcomes and quality of life for this large patient population of women.

Efficacy of uterine artery embolization (UAE) for uterine fibroids according to FIGO classification: a single-center experience.

OBJECTIVE: This study aims to retrospectively evaluate the outcomes of uterine artery embolization (UAE) for uterine fibroids (UFs), specifically submucosal UFs, according to the International Federation of Gynecology and Obstetrics (FIGO) classification of UFs. MATERIALS AND METHODS: Forty-two patients with symptomatic UFs underwent UAE with Embosphere® between July 2016 and November 2021. MRI was performed before, at 3 and 6 months after the UAE. At each examination, the volume of UF was measured, and the percentage volume reduction rate (VRR) was calculated. The technical success rate (TSR), symptom improvement rate (SIR), regrowth rate (RR) after 6 months, and adverse events (AEs) were examined; VRR was compared between patients with submucosal UFs (FIGO types 0-2, group A), those with submucosal contacts (FIGO type 3, group B), and those without submucosal UFs (FIGO types 4-7, group C). Statistical analysis was performed on the difference in VRR between groups A, B, and C at 3 and 6 months after UAE. The relationship with hormone levels before UAE and VRR was evaluated. RESULTS: Thirty-seven of the 42 patients were evaluated. Overall, VRR was 37.0% at 3 months and 52.1% at 6 months; TSR, SIR, and RR were 100%, 95.2%, and 5.4%, respectively; VRR at 6 months was 80.7% for group A (n = 7), 57.8% for group B (n = 13), and 37.1% for group C (n = 17). Significant differences were found between A and C (p < 0.001) and B and C (p = 0.023). Hormone levels before UAE had no effect on VRR. There was no significant AEs other than grade 3 pulmonary embolism in one patient. CONCLUSION: UAE was effective for submucosal FIGO types 0-3. UAE was especially useful as an option for FIGO type 3 with a low protrusion rate that is difficult to treat with transcervical resection.

Crucial factors for implementing treatment strategies in intractable atonic postpartum haemorrhage: early phase contrast medium extravasation on dynamic CT.

AIM: To identify the relationship between contrast medium extravasation (CME) on dynamic contrast-enhanced computed tomography (DCT) and clinical information in intractable atonic postpartum haemorrhage (PPH) and its relevance to treatment with uterine artery embolisation (UAE). MATERIALS AND METHODS: Of 90 patients who underwent DCT to diagnose PPH, 60 diagnosed with intractable atonic PPH were investigated retrospectively. Maternal background and clinical indicators were analysed to compare the positive and negative factors of early phase CME. Regression analysis was used to investigate the factors associated with CME. The sensitivity, specificity, and positive and negative predictive values of early phase CME for predicting UAE were calculated. Clinical outcomes were compared between the two groups according to the timing of the decision to undergo UAE. RESULTS: Of the 60 patients with intractable atonic PPH, 21 underwent UAE, 20 of whom had early phase CME on DCT. Pre-DCT clinical parameters and clinical indices were not significantly different in presence of early phase CME. Early phase CME was associated with UAE performance, with a sensitivity of 95%, specificity of 87%, positive predictive value of 80%, and negative predictive value of 97%. In cases where UAE was performed after conservative management, there was a significant increase in blood loss and transfusion volume. CONCLUSION: Early phase CME is not indicated by background factors or clinical findings. UAE is not required when CME cannot be detected in the uterine cavity. If early phase CME is present, UAE should be considered immediately.

Recurrence of Uterine Fibroids After Conservative Surgery or Radiological Procedures: a Narrative Review.

The present narrative review aims to discuss the available data on the incidence and the risk factors of uterine fibroids (UFs) recurrence after different types of conservative surgical or radiologic procedures in women wishing to preserve their uterus. UFs are the most common benign tumors in women all over the world. Clinical presentation, including abnormal uterine bleeding (AUB), pelvic pain, bulky symptoms, and infertility affect patients' quality of life, and a large variety of conservative treatments are available especially for those with desire of pregnancy. Fertility sparing surgery, by either laparoscopy, hysteroscopy or laparotomy, or radiological interventions (uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound), are the most common therapeutic approaches. However, the genetic or acquired predisposition to UFs remain despite the treatments, and the recurrences are frequently described in a large percentage of patients. The most relevant risk factors for recurrence of UFs are young age at the first surgery, incomplete fibroid resection, the presence of multiple lesions, an enlarged uterus, and the coexistence with other pelvic diseases. The discussion on the possible medical strategy to reduce the recurrence is an open field of clinical investigation, in particular by using hormonal drugs.