title: Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.
abstract: BACKGROUND
  Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF.
  
  
  METHODS
  In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured.
  
  
  RESULTS
  Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response.
  
  
  CONCLUSIONS
  pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: R L
authors.initials: RL
authors.lastname: O'Donnell
authors.forename: P
authors.initials: P
authors.lastname: Warner
authors.forename: R J
authors.initials: RJ
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Walker
authors.forename: L E
authors.initials: LE
authors.lastname: Bath
authors.forename: C J
authors.initials: CJ
authors.lastname: Kelnar
authors.forename: W H B
authors.initials: WH
authors.lastname: Wallace
authors.forename: H O D
authors.initials: HO
authors.lastname: Critchley
mesh_terms: D018592:Cross-Over Studies; D004717:Endometrium / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D012739:Gonadal Steroid Hormones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D016649:Primary Ovarian Insufficiency / Q000188:drug therapy*; D012039:Regional Blood Flow / Q000187:drug effects*; D055988:Uterine Artery / Q000187:drug effects / Q000502:physiology*; D014599:Uterus / Q000098:blood supply / Q000187:drug effects*
chemical_list: D012739:Gonadal Steroid Hormones; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone