title: Unscheduled bleeding during initiation of continuous combined hormone replacement therapy: a direct comparison of two combinations of norethindrone acetate and ethinyl estradiol to medroxyprogesterone acetate and conjugated equine estrogens.
abstract: OBJECTIVE
  To determine whether there are differences between continuous combined hormone replacement therapies on bleeding control.
  
  
  METHODS
  Nine hundred and forty-five postmenopausal women were randomized to one of seven double-blind treatment groups (placebo, 0.25 mg norethindrone acetate (NA)/5 microg ethinyl estradiol (EE), 1 mg NA/5 microg EE, 0.5 mg NA/10 microg EE, 1 mg NA/10 microg EE, 5 microg EE, and 10 micro EE) or unmasked 0.625 mg conjugated equine estrogens (CEE)/2.5 mg medroxyprogesterone acetate (MPA). Treatment was for 12 months; subjects kept daily diaries recording whether they had bleeding and/or spotting.
  
  
  RESULTS
  The results focused on currently commercially available hormone replacement therapy products (femhrt [1 mg NA/5 microg EE] and Prempro [0.625 mg CEE/2.5 mg MPA]) as well as a high-dose NA/EE dose combination (1/10) over the first 6 months of use, the most critical period in establishing treatment adherence. At the end of month 6 there was a greater incidence of amenorrhea with both NA/EE dose combinations compared with CEE/MPA (p = 0.009 for 1 mg NA/5 microg EE and p = 0.006 for 1 mg NA/10 microg EE). Statistically significantly more women were amenorrheic at every month based on cumulative amenorrhea for 1 mg NA/5 microg (p < 0.05) compared with CEE/MPA; at months 3 and 6 more women were amenorrheic on 1 mg NA/10 microg EE compared with CEE/MPA using the cumulative amenorrhea parameter.
  
  
  CONCLUSIONS
  The results indicate that statistically significantly more women attained amenorrhea based on various parameters when administered continuous combined NA/EE compared with CEE/MPA. The potential for long-term treatment compliance based on better bleeding control may optimize the opportunity to prevent osteoporosis as well as other associated health benefits.
authors.affiliation: Women's Health Research Center, Laurel, Maryland, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Simon
authors.forename: J P
authors.initials: JP
authors.lastname: Symons
mesh_terms: D004338:Drug Combinations; D045166:Estradiol Congeners / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D008593:Menopause / Q000187:drug effects*; D008875:Middle Aged; D009640:Norethindrone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000077563:Norethindrone Acetate; D045167:Progesterone Congeners / Q000494:pharmacology*
chemical_list: D004338:Drug Combinations; D045166:Estradiol Congeners; D004966:Estrogens, Conjugated (USP); D045167:Progesterone Congeners; D004997:Ethinyl Estradiol; D000077563:Norethindrone Acetate; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone