The Use of Nomegestrol Acetate in Rapid Preparation of Endometrium Before Operative Hysteroscopy in Pre-Menopausal Women

Steroids 75 (2010) 912–917

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The use of nomegestrol acetate in rapid preparation of endometrium before operative hysteroscopy in pre-menopausal women

Pasquale Florio a,∗, Alberto Imperatore a, Pietro Litta b, Mario Franchini c, Stefano Calzolari c, Stefano Angioni d, Massimo Gabbanini a, Luca Bruni a, Felice Petraglia a a Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Obstetrics and Gynecology, University of Siena, Policlinico ‘Le Scotte’, Viale Bracci, 53100 Siena, Italy b Department of Gynecological Science and Human Reproduction, University of Padua, School of Medicine, Padua, Italy c Palagi Free-Standing Unit, Florence, Italy d Department of Surgery, Maternal–Fetal Medicine, and Imaging Sciences, Unit of Gynecology, Obstetrics and Physiopathology of Human Reproduction, University of Cagliari, Cagliari, Italy article info abstract

Article history: The presence of a thin endometrium has an important role in allowing the best conditions for hys- Received 24 February 2010 teroscopic surgery. Here, we explored the efﬁcacy of a 14-day administration of nomegestrol acetate, Received in revised form 12 May 2010 a progestogen with high progestogen potency effects, in rapid endometrial preparation to operative Accepted 13 May 2010 hysteroscopy. Available online 26 May 2010 A total of 86 fertile women selected for operative hysteroscopy received for 14 days either 5 mg day−1 of nomegestrol acetate (n = 43; group A) or 4 mg day−1 of folic acid (n = 43; group B), starting on day 1 of the Keywords: subsequent menstrual cycle. Before treatments on days 12–14 of the menstrual cycle, all patients under- Hysteroscopy Endometrium went endometrial thickness measurement; ultrasonography of the ovaries to measure the appearance Progestins of a dominant follicle; diagnostic hysteroscopy with endometrial biopsy; plasma estradiol (E2), proges- HPA-axis terone (P), luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels measurements. On Surgery the day of surgery, patients repeated endometrial and ovarian ultrasonography and, E2, P, LH and FSH measurement. At enrolment, endometrial thickness, mean follicular diameter and E2, P, LH and FSH concentrations did not differ between groups. At the time of operative hysteroscopy (i.e., after 14 days’ treatment) group A, but not group B, showed signiﬁcant (all P < 0.001) reduction of endometrial thickness, mean diameter of dominant follicle, E2, P and LH concentrations. Endometrial preparation was judged more effective in group A than B, since the endometrial mucosa in all of the women of group A appeared to be very thin, hypotrophic, regular and pale. In conclusion, administration of nomegestrol acetate was effective in reducing endometrial thickness, also acting on the hypothalamus–pituitary–ovarian axis, thus allowing highly favourable operative hysteroscopic conditions. © 2010 Elsevier Inc. All rights reserved.

1. Introduction Hysteroscopic surgery has changed the surgical landscape, reducing procedural and postoperative morbidity, with clear benefits for Blind sampling with dilatation and curettage of the uterine cav- patients [1]. ity was, until recently, a routine procedure in gynaecology. With In fertile women, preoperative pharmacologic treatment has the advent of advanced optics, safer distension techniques and been recommended to reduce endometrial thickness, intra- adequately trained surgeons, hysteroscopy is now the established operative bleeding, surgical difficulties and duration of surgery ‘gold standard’ for the assessment and management of intrauterine [5–7]. Among the several drugs proposed in the past years, pathology, and is regarded as a safe, acceptable and well-tolerated gonadotrophin releasing hormone (GnRH) analogues have been procedure [1–4]. Its therapeutic indications extend to resection suggested for removal of large intramural submucous myomas of submucous myomas, fibroid and polyps, division of intrauter- or endometrial resection [8], due to their effect in thinning the ine septum and intrauterine synechiae, endometrial resection and endometrium. However, they are not as often used for procedure ablation, directed biopsy and removal of a lost intrauterine device. preparation, especially in cases of ‘minor’ hysteroscopy surgery, because they result in a state of temporary menopause and, not last, due to the cost [9]. Further, danazol, a medication usually ∗ Corresponding author. Tel.: +39 0577 586649; fax: +39 0577 233454. used for endometriosis treatment, at a daily dosage of 400 mg E-mail address: fl[email protected] (P. Florio). orally for 6 weeks, is able to induce endometrial atrophy, reducing

0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2010.05.009 P. Florio et al. / Steroids 75 (2010) 912–917 913 consequently the thickness of the endometrium as well as its vas- surement, or where no dominant follicle was detected. Therefore, cularisation. However, despite it being less expensive than GnRH 24 women were excluded for the following reasons: fibroids (n = 7); analogues, its anti-oestrogenic activity and androgenic propen- concurrent hormonal therapies (n = 3); uterine and/or concomi- sity could induce unfavourable side effects including weight gain, tant adnexal pathologies (n = 2); cardiovascular (n = 3) or hepatic growth of hair, acne and general malaise [9]. (n = 1) impairment; adhesions (n = 3), septa (n = 2) or uterine posi- Another limiting factor among existing treatments for endome- tion (n = 1); and the absence of dominant follicle (n = 1). The data trial preparation is the long time required to efficiently reduce the from the remaining 86 were considered for the study. The Institu- endometrium; other than that, they could be costly and be accom- tional Review Board approved the study, and all patients received panied by clinical drawbacks. The search for a new treatment able detailed information about the study and the surgical procedure, to overcome most of the previously encountered disadvantages is to which they gave their consent. mandatory to improve patient acceptability of the hysteroscopic procedure and work organisation for medical staff. 2.1. Study protocol Nomegestrol acetate, a progestogen designed to have no androgenic or oestrogenic actions and high progestogen potency effects, The women became eligible for treatment sequentially, and as shares several pharmacological properties that can be considered such they were randomly assigned to receive for 14 days, starting on useful in the pre-surgery endometrial preparation [10,11]. Indeed, day 1 of the subsequent menstrual cycle, 5 mg day−1 per 14 days of studies have shown that nomegestrol acetate has little effect on nomegestrol acetate (Lutenyl, Theramex, Italy) administered each carbohydrate, lipid or hepatic metabolism, and it is able to reduce day by oral route at bedtime (group A) or 4 mg day−1 per 14 days of endometrial thickness, uterine volume and menorrhagia without commercially available folic acid (Folanemin, Theramex, Italy) by significant side effects [10–14]. oral route at the same time (group B), using the sequential treat- In the present study, we evaluated whether preoperative oral ment assignment with balancing for prognostic factors [15]. The administration of nomegestrol acetate in women with endometrial procedure ensures treatment groups of equal size (n = 43 for both polyps is able to reduce endometrial thickness and difficulties in nomegestrol acetate and folic acid treatments) as well as the bal- hysteroscopic surgery. ance across the treatments of the effects of prognostic factors [15]. The person responsible for patient selection and drug dispensing 2. Materials and methods was blind to whether the next patient would receive nomegestrol acetate or folic acid. A flowchart of the study is presented in Fig. 1. Between March 2007 and November 2008, we identified 110 At enrolment (on days 12–14 of the menstrual cycle), all patients pre-menopausal women, who had reported regular menstrual underwent SIS evaluation of their uterine cavity with endometrial cycle rhythms for the previous 6 months, and in whom sonohys- thickness measurement; ultrasonography of the ovaries to measure terosalpingoscophy (saline-infusion sonohysterography, SIS) and the appearance of a dominant follicle; diagnostic hysteroscopy with diagnostic hysteroscopy with endometrial biopsy, performed on endometrial biopsy; blood sampling for measurements of plasma days 12–14 of the menstrual cycle, indicated the presence of end- estradiol (E2), progesterone (P) luteinising hormone (LH) and outerine polyps (Table 1). The following exclusion criteria were follicle-stimulating hormone (FSH) levels. On the day of surgery, applied: presence of fibroids; hormonal therapies in the previ- patients repeated ultrasound exam to measure endometrial thick- ous 8 weeks; uterine and/or concomitant adnexal pathologies; ness and ovarian features and blood sampling for measurements of cardiovascular, hepatic or renal impairment; and any medical con- plasma E2, P, LH and FSH levels. dition that would have increased the surgical risk [3]. The study also excluded all cases where the presence of adhesions, septa or 2.2. Hormone measurements uterine position prevented a reliable endometrial thickness mea- Hormone (FSH, LH, E2 and P) measurements were per-

Table 1 formed with commercially available kits (Diagnostic Systems Anthropometric and clinical findings related to women belonging to group A Laboratories), with intra- and inter-assay coefficients of variation (nomegestrol acetate) and group B (placebo). Data are presented as mean ± SD. BMI: determined by the manufacturer with routine quality control mate- body mass index. rial <10%. Group A Group B P value (n = 43) (n = 43) 2.3. Saline-infusion sonohysterogram (SIS) Age 29.3 ± 6.7 28.1 ± 6.9 0.42 BMI 22.5 ± 1.4 22.6 ± 2.5 0.82 Patients were placed in the dorsal lithotomic position, a stan- Parity (range) 1 (0–3) 1 (0–3) 1.0 dard bivalve speculum was inserted and, the uterine cervix was ± ± Endometrial polyps diameter (mm) 1.8 0.5 1.9 0.7 0.45 cleansed with an antiseptic solution (povidone–iodine). A paedi- Endometrial thickness (mm) atric Foley catheter was inserted into the uterine cavity through At enrollment 6.4 ± 1.0 6.0 ± 1.2 0.1 After treatment 3.9 ± 0.2a 6.2 ± 0.6b 0.000 the cervical os until it reached the fundus and the balloon of Ovarian follicle diameter (mm) the catheter was inflated with 2 ml of normal saline solution. At enrollment 15.2 ± 0.9 14.8 ± 1.2 0.08 The speculum was then withdrawn and a transvaginal ultrasound ± c ± d After treatment 9 0.8 15.0 1.4 0.000 (5 MHz) probe introduced. Up to 20 ml of sterile saline solution was Hormone concentrations at enrollment LH (IU l−1) 5.23 ± 0.33 5.12 ± 0.21 0.07 infused into the uterine cavity; 5–10 ml usually proved to be suffi- FSH (IU l−1) 4.7 ± 0.6 4.8 ± 0.4 0.37 cient to distend the cavity, and the distended cavity was observed E2 (pg ml−1) 98.7 ± 14.7 101.3 ± 16.6 0.44 directly by sonography. The same volume solution (20 ml) was then −1 P (ng ml ) 7.5 ± 1.7 8.2 ± 2.3 0.11 gradually flushed into the uterine cavity via the opening connected Hormone concentrations after treatment − to the inner lumen allowing visualisation of endometrial diseases. LH (IU l 1) 3.43 ± 0.11e 5.22 ± 0.31f 0.000 FSH (IU l−1) 6.1 ± 0.3g 4.8 ± 0.6h 0.000 Afterwards, gentle suction via the same opening was applied to E2 (pg ml−1) 21.1 ± 5.1i 101.4 ± 15.2j 0.000 recover the fluid. The location and size of any uterine abnormali- − P (ng ml 1) 1.9 ± 0.3k 7.9 ± 0.4l 0.000 ties were noted. The anterior and posterior endometrial thicknesses a,c,e,g,i,k: P = 0.000 vs value at enrolment. were measured as the maximal distance between the two myome- b,d,f,h,j,l: P > 0.05 vs value at enrolment. trial interfaces in a longitudinal scan, ensuring avoidance of the 914 P. Florio et al. / Steroids 75 (2010) 912–917

Fig. 1. Flow diagram of the clinical trial.

Fig. 2. Changes of circulating levels of E2, P, LH, and FSH before and after 14 days treatment of nomegestrol acetate (group A, gray bars) or placebo (folic acid, group B, open bars). P. Florio et al. / Steroids 75 (2010) 912–917 915 polyp in the measurement and then in the transverse plane from haemorrhage required immediate suspension of hysteroscopy. the cervix to the fundus. These two measurements were added to Measurements of inflow, outflow and amount of distension liquid calculate the total endometrial thickness. absorbed by the patient were taken meticulously. At the time of surgery, the surgeon’s satisfaction with the 2.4. Diagnostic hysteroscopy endometrial preparation was evaluated by asking the surgeons who was unaware of the treatment to score the degree of satisfaction Office hysteroscopy was performed using the vaginoscopy with the preparation by marking a 10-cm visual analogue scale approach, with office hysteroscopy using Telescope 2.9 mm (HOP- from 0 (minimal) to 10 (optimal). An unbiased and independent KINS II Forward-Oblique Telescope 30◦; Karl Storz, Tuttlingen, person not involved in the procedures of the study itself docu- Germany) and continuous flow sheath. The uterine cavity was mented and scored differences between the two treatments. distended with physiological solution and irrigated using an electronic irrigation pump (Hysteromat, Karl Storz®, Karl Storz, 2.7. Statistical analysis Tuttlingen, Germany). Examination was performed as an office procedure, without anaesthesia or cervical dilatation. During diag- All data were analysed with Prism software (GraphPad Software nostic hysteroscopy, all patients underwent endometrial biopsy for Inc., San Diego, CA, USA), and were expressed as mean ± SD (range) histological classification of endometrial tissue and to exclude any or as number (%) of cases. The Kolmogorov–Smirnov test was used possible malignancy [16]. to evaluate whether values had a Gaussian distribution, in order to choose between parametric and non-parametric statistical tests. To 2.5. Operative hysteroscopy compare data between the two groups, Student’s t-test was used for parametric data and the Mann–Whitney test for non-parametric Patients were hospitalised the same day of surgery that was data. Dichotomous variables were analysed with the 2 test and performed in the morning, 10–12 h after the last assumption of the Fisher’s exact test, when appropriate. P < 0.05 was considered nomegestrol or placebo. Electrocardiogram and routine blood tests statistically significant. were performed on the day of surgery, and side effects experienced by patients during treatment were recorded. 3. Results Operative hysteroscopy was performed in the inpatient day surgery under general anaesthesia by members who had compa- The two study groups were similar for age, parity and body rable levels of experience and who were blind to the preoperative mass index (BMI), as well as for incidence and volume of uterine treatment allocated. After the cervical canal was dilated to a Hegar cavity pathologies (P > 0.05) (Table 1). Nevertheless, no differences dilator of size 10 or 11 mm, a rigid monopolar resectoscope with a were retrieved at enrolment between groups in terms of endome- 10-mm outer sheath diameter and 30◦ forward-oblique lens fitted trial thickness (group A: 6.4 ± 1.0 mm; group B: 6.0 ± 1.2 mm; with a cutting loop electrode at a power setting of 100 W cut- P = 0.1); mean follicular diameter (group A: 15.2 ± 0.9 mm; group ting current was used (Karl Storz GmbH, Tuttlingen, Germany). The B: 14.8 ± 1.2 mm; P = 0.08) and; concentrations of E2 (group A: uterine cavity was distended with 1.5% glycine solution at an insuf- 98.7 ± 14.7 pg ml−1; group B: 101.3 ± 16.6 pg ml−1; P = 0.44), P flation pressure of 80–100 mm Hg, with careful monitoring of fluid (group A: 7.5 ± 1.7 ng ml−1; group B: 8.2 ± 2.3 ng ml−1; P = 0.11); LH balance. The first step in the exploration of the uterine cavity con- (group A: 5.23 ± 0.33 IU l−1; group B: 5.12 ± 0.21 IU l−1; P = 0.07); sisted of a panoramic view of the cavity; next was the examination and FSH (group A: 4.7 ± 0.6 IU l−1; group B: 4.8 ± 0.4 IU l−1; P = 0.37) of both cornua, tubal ostia and anterior and posterior walls. (Table 1; Fig. 2). At the time of surgery, endometrial appearance was assessed On the contrary, significant changes were observed after 14 by direct vision and was classified, according to criteria reported days of treatment with nomegestrol acetate (group A) or placebo by Baggish and Barbot [17], as ‘normal’ if compatible with a nor- (folic acid, group B), since mean endometrial thickness after treat- motrophic endometrium; ‘hypotrophic with normotrophic areas’ ment was significantly (P < 0.001) smaller in group A (3.9 ± 0.2 mm) if not completely atrophic; and ‘atrophic’ if completely atrophic. than in group B (6.2 ± 0.6 mm), as well as the mean diame- An endometrial sample was taken from each patient by resection ter of the dominant follicle (group A: 9.0 ± 0.8 mm; group B: so that the visual evaluation could be compared with a histologic 15.0 ± 1.4 mm; P < 0.0001). Moreover, whilst no difference was examination at the time of surgery and that found at the time of retrieved in endometrial thickness and follicle diameter in group B enrolment. After the operation, the women remained in hospital before and after placebo assumption, in women belonging to group for a minimum of 6 h and attended a follow-up visit after 6 weeks. A, there was a significant (both P < 0.001) reduction of both param- eters from enrolment to the time of operative hysteroscopy (i.e., 2.6. Outcomes measure after 14 days treatment with nomegestrol acetate) (Table 1; Fig. 1). With respect to hormones, the concentrations of E2 We compared outcome measures between days 12 and 14 of (21.1 ± 5.1 pg ml−1), P (1.9 ± 0.3 ng ml−1) and LH (3.43 ± 0.11 IU l−1) the untreated cycle and at the same time in the treated cycle. Out- were significantly (P = 0.000 for all) lower in group A than in come measures were changes before and after treatments of: (i) group B (E2: 101.4 ± 15.2 pg ml−1;P:7.9± 0.4 ng ml−1; LH: endometrial thickness and ovarian follicle dimensions; (ii) circu- 5.22 ± 0.31 IU l−1), whilst FSH levels were significantly (P = 0.000) lating concentrations of pituitary (LH and FSH) and ovarian (E2 and higher (6.1 ± 0.3 IU l−1) in group A than group B (4.8 ± 0.6 IU l−1) P) hormones; and (iii) endometrial appearance both at diagnostic (Table 1; Fig. 1). Again, in group B, no difference was retrieved and operative hysteroscopy. Details regarding the time required in hormone levels before and after treatment, whilst women for each cervical dilatation and the duration of surgical procedure belonging to group A had significant (all P < 0.001) variations of all (from the insertion to the removal of the resectoscope); surgi- hormonal values after 14 days of nomegestrol acetate assumption cal associated side effects (postoperative complications occurring (Table 1; Fig. 2). Women had elevated levels of serum P in the con- during from the termination of surgery to discharge 4–5 h after trol cycle on days 12–14, which were suppressed with the nomege- surgery); and side effects experienced by patients during treatment strol acetate in the treatment cycle on days 12–14 (Table 1; Fig. 2). were also recorded. Intra-operative bleeding was defined, as ‘light’ Table 2 refers to data collected at hysteroscopy. At enrol- when bleeding did not interfere with surgery, ‘moderate’ when ment, there was good correlation among histological examination, bleeding required the coagulation of vessels and ‘severe’ when anamnestic data regarding the last menstrual cycle and, visual 916 P. Florio et al. / Steroids 75 (2010) 912–917

Table 2 treatment would rely on the fact that nomegestrol acetate is a Findings related to the surgical procedure in groups A and B. Data are presented as progestational molecule that binds almost exclusively to the pro- mean ± SD. gesterone receptor and does not interfere with the other steroid Group A (n = 43) Group B (n = 43) P value receptors, thus avoiding androgenic, oestrogenic or glucocorticoid Operating time (min) 12.6 ± 1.8 13.2 ± 1.4 0.09 side effects [10–14]. Indeed, nomegestrol acetate is one of the pro- Infusion volume (ml) 1100 ± 120 1170 ± 230 0.08 gestins possessing methyl groups in the 19 position, which confers Cervical dilatation (min) 2.0 ± 0.1 2.1 ± 0.6 0.28 upon it no oestrogenic activity [18,19], bind properties for oestro- Intra-operative bleeding, no. gens receptor [20,21]. Nevertheless, nomegestrol acetate is also Severe 0/43 0/43 1.0 able to block the enzymes involved in oestradiol biosynthesis (sul- Light 8/43 22/43 0.04 phatase, 17-hydroxysteroid dehydrogenase) [22,23] and, simulta- Moderate 01/02/43 11/43 0.04 neously, to reduce the cellular level of oestrogens receptor (ER) Surgeons satisfaction 8.2 ± 1.6 6.4 ± 1.2 0.000 mRNA by decreasing the transcription of the ER gene [19,20,22–25]. Postoperative complications The present findings and our data related to nomegestrol acetate Headache 0/43 0/43 1.0 ability in lowering endometrial thickness together would suggest Nausea 1/43 0/43 1.0 that the activity of nomegestrol acetate is mainly directed on the Swelling 0/43 0/43 1.0 endometrial target. However, in the present study, we found that the administration of nomegestrol acetate was also associated with changes in the activity of the hypothalamus–pituitary–ovarian appearance, since all patients were in the proliferative phase of axis, since its administration was associated with the reduction the menstrual cycle. Assessment of endometrium at the time of of LH, E2 and P concentrations, and inhibition of folliculogenesis. surgery showed that all patients responded to the treatment with a These data confirm previous findings on the antiovulatory ability of significant difference between groups. Indeed, surgeon satisfaction nomegestrol acetate that would act at the pituitary level where the in terms of endometrial preparation was statistically significantly progesterone receptor is expressed only in gonadotroph cells [26]. (P < 0.001) higher for women of group A (8.2 ± 1.6) compared The anti-gonadotropic activity of nomegestrol acetate, together with group B (6.4 ± 1.2), since at hysteroscopy, the endometrial with its anti-oestrogenic effect locally on the endometrium, can mucosa in all of the women of group A appeared to be very thin, help us in explaining the concordance between visual appearance hypotrophic, regular and pale. On the contrary, the endometrial at hysteroscopy and biochemical (changes in hormones related surface in group B was high and irregular, with areas of stromal to ovulation) and biophysical (ultrasonographic data related to oedema and glandular development. changes in endometrial thickness) measures. Indeed, we found No significant differences emerged in relation to time taken for that the endometrial mucosa of women treated by nomegestrol cervical dilatation (group A: 2.0 ± 0.1 min; group B: 2.1 ± 0.6 min; acetate appeared to be very thin, hypotrophic, regular and pale. P = 0.28); total operating time (group A: 12.6 ± 1.8 min vs group This finding is not surprising, since it was already reported B: 13.2 ± 1.4 min; P = 0.09); and infusion volume used (group A: that the endometrium of women in whom nomegestrol acetate 1100 ± 120 ml; group B: 1170 ± 230 ml; P = 0.08) (Table 2). No inhibited ovulation had features similar to those depicted by the cases of severe intra-operative bleeding occurred in either group; present study. The presence of a thin endometrium may also however, the prevalence of light and moderate bleeding was signif- explain the low prevalence of bleeding in patients treated by icantly (P < 0.05 for both) higher in group B than group A (Table 2). nomegestrol acetate undergoing hysteroscopy preparation. Thus, Both groups showed no postoperative complications after surgical the appreciable reduction of endometrial vascularity obtained procedure. using nomegestrol acetate may also contribute to lowering the Finally, the use of nomegestrol acetate was well tolerated and risk of operative liquid absorption and, consequently, lower risk no side effects (headache, nausea and swelling) were reported by of electrolytic alterations. The possibility of existing inter-patient any of the patients referring to the pre-surgery treatment interval variation of pre-treatment endometrial thickness altering the com- (Table 2). parison of treatment effects, thus representing a limitation of the study, was overcome by the visual appraisal obtained at diagnostic 4. Discussion hysteroscopy and the meticulous measurement of endometrial thickness performed during SIS in the pre-treatment period the The presence of a thin endometrium has an important month before surgery. Although it cannot be excluded that some role in allowing the best operative conditions in hysteroscopic variations could occur in the endometrial thickness in the same surgery and, for this reason, diagnostic or operative procedures patient at the same days of different cycles, it is unlikely that the are scheduled in the immediate post-menstrual phase, as the natural variations could significantly affect the study results. most favourable physiological condition associated with reduced In conclusion, our data suggest that pre-surgical treatment with endometrial thickness. Due to the difficulties often encountered in nomegestrol acetate could provide a fast, satisfactory and low-cost reliably arranging surgery for this time, various hormonal agents preparation of the endometrium before surgery, thus improving have been used to reduce endometrial thickness [9]. The rationale surgical performance and patients’ compliance. The mechanisms of their use is based on the ability to reduce endometrial growth and by which nomegestrol acetate induces this effect may be related vascularity, thus causing endometrial atrophy, due to their anti- to a suppressive effect on follicular development and anovulation oestrogenic, as in the case of GnRH analogues, or androgenic, as in through an inhibitory regulation of GnRH, participating in the con- the case of danazol, activities [9]. trol of gonadotropin release also at the pituitary level, as well as In the present study, we explored the efficacy of nomege- suppressing of endometrial growth as seen by transvaginal sonog- strol acetate in rapid endometrial preparation to operative raphy, which accounts for the reduction in endometrial thickness hysteroscopy. 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