OBJECTIVE: To compare the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) and oral norethisterone acetate (NET) for treatment of non-atypical endometrial hyperplasia in perimenopausal women. METHODS: One hundred and twenty perimenopausal women with non-atypical endometrial hyperplasia were selected in this randomized controlled trial. Patients received LNG-IUS (n=59) or NET (n=61; 15 mg/day for 3 weeks/cycle) for 3-6 months. Outpatient follow-up with endometrial biopsies were undertaken at 3, 6, and 12 months intervals after treatment. Outcome measures were; the regression rate, the time to regression and hysterectomy rate. RESULTS: A significantly higher regression rate was noted in the LNG-IUS group than in NET group at the 3rd, 6th and 12th month follow-up visits using intention-to-treat analysis (67.8% vs. 47.5%, relative risk [RR], 1.42; 79.7% vs. 60.7%, RR, 1.31; and 88.1% vs. 55.7%, RR, 1.58, respectively). However, no significant difference was found regarding the median time to regression (3 months). The hysterectomy rate during the follow-up period was significantly higher in the NET group (57.4% vs.22%, p<0.001). CONCLUSION: LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women is more effective than NET for achieving disease regression for the majority within 1 year. Moreover, it can reduce the number of hysterectomies performed.
Biopsy ; Endometrial Hyperplasia ; Female ; Follow-Up Studies ; Humans ; Hysterectomy ; Norethindrone ; Outcome Assessment (Health Care) ; Outpatients

OBJECTIVE: To compare the efficacy of different add-back regimens on hypoestrogenic symptoms during postoperative gonadotropin-releasing hormone (GnRH) agonist treatment in endometriosis patients. METHODS: This 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. RESULTS: A 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. CONCLUSION: This 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.
Bone Density ; Cohort Studies ; Endometriosis* ; Estradiol ; Female ; Gonadotropin-Releasing Hormone* ; Humans ; Incidence ; Laparoscopy ; Norethindrone ; Prospective Studies ; Quality of Life ; Spine

OBJECTIVES: To evaluate the effects of progesterone/progestin and in combination with estrogen in relaxation of rat aorta. METHODS: Eight weeks after bilateral oophorectomy, the descending aorta of Spague-Dawley rats (n=10) were quickly removed and placed in organ bath containing Krebs solution. Each aorta ring in 2-3 mm length was connected to an isometric force transducer (FT 03, Grass, USA) and the changes in tension were recorded with an AD converter system (MP 100, Biopac Inc, USA) in a personal computer. After precontraction of the rings with norepinephrine (1 umol/L) or KCl (40 mmol/L), estradiol, progesterone, medroxyprogesterone acetate (MPA), norethisterone acetate (NETA) (10-5-10-8 M/L in each) were added to each ring and they were incubated for 15 minutes. The relaxation was expressed as a percentage of the tonic contraction. RESULTS: Estrogen relax the aorta in all concentrations. The degree of relaxation was dose dependent (P<0.001). All of the progesterone, MPA, NETA relax the aorta and the effects was different according to the concentration of steroids (P<0.0001). The degree of relaxation was not different between estrogen and those of progesterone, MPA, NETA except MPA 10-8 M, NETA 10-5 M. Addition of progesterone, MPA and NETA to the estrogen showed similar vascular effects compared to those of estrogen alone. CONCLUSION: Not only estrogen but also progesterone, MPA, and NETA acutely relax aorta. Progesterone/progestin have not been found attenuate the action of estrogen in our animal in vitro study.
Animals ; Aorta ; Aorta, Thoracic ; Arteries ; Baths ; Estradiol ; Estrogens ; Female ; Medroxyprogesterone Acetate ; Microcomputers ; Norepinephrine ; Norethindrone ; Ovariectomy ; Poaceae ; Progesterone ; Rats ; Relaxation ; Steroids ; Transducers

In view of continuous clinical reports of liver damage following oral contraceptive use, morphologic changes of the liver following the administration of a combined type of oral contraceptive (Norinyle) were studied in guinea pigs by light and electron microscopic examinations. Two interesting changes, one in Kupffer cells and another in the hepatocytes were observed. The Kupffer cells were hyperplastic and enlarged due to the phagocytosis of a large amount of fibrin which were apparently formed intravascularly and were being cleared by Kupffer cells. It is thought that enlarged Kupffer cells and excessive fibrin formation beyond the clearing capacity of Kupffer cells may lead to blockage of sinusoids resulting in a Budd-Chiari like syndrome. The nucleus of the hepatocytes showed mild enlargement and a clear nucleolar segregation which is regarded as one of the ultrastructural evidences of chemical carcinogenesis. Therefore, it is speculated that this change may be related to tumorigenesis in the liver following oral contraceptive administration. Other changes consisted of ischemic necrosis and fatty changes in occasional animals, alteration of mitochondrial configuration and hyperplasia of smooth endoplasmic reticulum in hepatocytes.
Animal ; Blood Coagulation/drug effects ; Contraceptives, Oral/adverse effects* ; Contraceptives, Oral, Combined/adverse effects* ; Guinea Pigs ; Liver/drug effects ; Liver/pathology* ; Liver/ultrastructure ; Mestranol/adverse effects* ; Norethindrone/adverse effects*

OBJECTIVE: Observational studies showed a significant reduction in cardiovascular disease (CVD) among postmenopausal hormone replacement therapy (HRT) users. But recent randomized clinical trial reported that HRT does not decrease, and may in fact, increase the incidence of CVD. Progestogen may in part contribute the increased risk but the exact role of different progestogens in the development of CVD is still unclear. The aim of this study was to investigate the effects of progesterone/progestogen and combination with estrogen on the regulation of estrogen and progesterone receptor m RNA expression in vascular endothelial cells to provide a basis to analyze the direct steroid effects on CVD. METHODS: Human Umbilical Vein Endothelial Cells (HUVEC) were cultured for 24 hours. Media were supplemented with estradiol (E2) (10(-7)M), progesterone (P4) (10(-7)M), medoxy-progesterone acetate (MPA) (10(-7)M), norethindrone acetate (NETA) (10(-7)M) and RU 486 (10(-6)M) alone or in combination. Receptor expression (estrogen receptor alpha and progesterone receptor total and isoform B) was examined at the mRNA level by reverse transcription-PCR. RESULTS: Total progesterone receptor expression was decreased after NETA treatment. E2, P4, MPA, NETA increased expression of PRB. PRB expression was more increased in E2 combined with P4 and MPA, than single treatment. PRB down regulation was found when RU 486 was additionally supplemented into the medium. ER expression was decreased after E2, P4, and MPA treatment. When MPA was added to E2, ER was more down reguated than the addition of P4 and NETA. RU 486 prevented down reguation of MPA on ER alpha. CONCLUSION: These findings suggested that MPA compared to P4 and NETA, may attenuate the favorable effect of estrogen on vasular endothelium.
Cardiovascular Diseases ; Down-Regulation ; Endothelial Cells ; Endothelium ; Estradiol ; Estrogen Replacement Therapy ; Estrogens* ; Female ; Hormone Replacement Therapy ; Human Umbilical Vein Endothelial Cells* ; Humans* ; Incidence ; Mifepristone ; Norethindrone ; Progesterone* ; Progestins ; Receptors, Progesterone* ; RNA ; RNA, Messenger

OBJECTIVE: The addition of progesterone/progestin is mandatory in women with intact uterus for postmenopausal hormone replacement therapy. However, debate is continuing on whether there is an impact of progesterone/progestin on the hormone replacement therapy for cardiac protection. The aim of this study was to investigate the effect of progesterone/progestin and combination with estrogen on the apoptosis of vascular endothelial cells, which has been demonstrated to be an initial step in the development of atherosclerosis. MATERIAL AND METHODS: Human Umbilical Vein Endothelial Cells (HUVEC) were cultured. HUVEC apoptosis was induced by Tumor Necrosis Factor-alpha (TNF-alpha) (50 ng/ml). 10-7M of estradiol (E2), progesterone (P4), medroxyprogesterone acetate (MPA) and norethindrone acetate (NETA) were added in to the culture media. The percentage of apoptotic HUVEC were measured by 3-[4,5-Dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) assay and Fluorescence Activated Cell Sorting (FACS) analysis. RESULTS: MTT assay demonstrated a significant decrease in percent of survival cells after 24 hours of TNF-alpha exposure and a reversal of the effect of TNF-alpha with E2 treatment. P4, MPA and NETA treatment also reversed the effect of TNF-alpha. The protective effect of E2 and P4 were not different. Compared to the E2 treatment, the percent of survival cell were decreased when P4, MPA and NETA were added to E2 treatment, respectively. Similarly, FACS analysis revealed 44.0+/-2.6% apoptosis after 24 hours of TNF-alpha exposure. Treatment with E2 resulted a significant decrease (28.4+/-2.9%, P<0.05) in apoptosis. P4 (33.6%+/-2.6%, P<0.05), MPA (35.7+/-1.3%, P<0.05), NETA (34.0+/-3.3%, P<0.05) treatment also showed a reduction of cell death. The percent of apoptotic cells between E2 and MPA treatment was significantly different. The addition of P4 (36.0+/-2.5%), MPA (36.3+/-1.9%) and NETA (37.0+/-2.0%) to E2 treatment significantly increased the percent of apoptotic cells compared to those of E2 treatment. CONCLUSION: These results suggested that not only estradiol, but also progesterone, MPA and NETA inhibited HUVEC apoptosis. But the effect of estrogen on the inhibition of HUVEC apoptosis was attenuated in combination treatment of estrogen and progesterone/progestin.
Apoptosis* ; Atherosclerosis ; Cell Death ; Culture Media ; Endothelial Cells* ; Estradiol ; Estrogen Replacement Therapy ; Estrogens ; Female ; Flow Cytometry ; Hormone Replacement Therapy ; Human Umbilical Vein Endothelial Cells ; Humans* ; Medroxyprogesterone Acetate ; Norethindrone ; Progesterone ; Tumor Necrosis Factor-alpha ; Umbilical Veins* ; Uterus