Hormone Replacement Therapy

I. Clinical presentation: sx may last for a year or more before cessation of menses; avg. age at cessation of menses 50-51yo

  1. Altered menses
  1. Decrease in interval between menses and decrease in amount and duration of flow is most common
  2. Increase in interval between menses to 35-38d
  3. 10-20% will have increased amount and duration of flow
  4. A few will simply have cessation of menses
  5. Any diversion from these patterns (e.g. no period x 2 mos then some bleeding) must be treated as abnormal
  1. Low estrogen sx
  1. Urogenital atrophy and dryness, occ. causing urethral sx-occur late
  2. Vasomotor disturbances-occur early
  1. 75% will get
  2. In 25%, persist for > 5y
  3. Seem to correspond to the exaggerated pulsatile release of FSH and LH from pituitary that results from decreased feedback inhibition from ovary; may actually result from hypothalamic stimulation of thermoregulatory centers, etc. simultaneous with secretion of GnRH
  1. ?Possibly, mood disturbance-unclear if responds to hormone replacement (see below)
  1. Menopause occurs in 90% of women by age 54y for smokers and 56y for nonsmokers (Am. J. Epidem. 117:651, 1983)

II. Diagnostic evaluation: combination of the first 3 are generally considered confirmatory:

  1. Amenorrhea > 3mos
  2. Signs/sx of estrogen deficiency
  3. FSH--goes up as menopause approaches; 40pg/ml is usual cut-off
    1. Increases before LH, because of decreased ovarian production of inhibin, a glycoprotein hormone that selectively inhibits secretion of FSH
    2. Since postmenopausal hormone replacement doesn't include inhibin, can't reliably use FSH measurements to determine adequacy of estrogen replacement!
    4. There is considerable overlap in FSH levels for women at different reproductive stages, such that FSH is not a reliable indicator of menopause (Menopause 13:171, 2006--JW)
  4. Vaginal pH > 4.5
    1. In a systematic review of studies of vaginal pH and menopause, mean vaginal pH in postmenopausal women (i.e. no menses x > 12mos) was 6.0 if not on estrogen therapy (4.5 if they were); pH > 4.5 in absence of estrogen therapy had PPV of 89% for menopause (Am. J. Obs. Gyn 190:1272, 2004--AFP)

III. Alternatives to HRT for tx of menopausal sx (for women that don't want HRT)

  1. Clonidine-little evidence for efficacy as of 2005
  2. Progestins, e.g. megestrol acetate
  3. Lubricants for vaginal dryness
  4. Serotonin Reuptake Inhibitors
    1. In a study in 200 women with a h/o breast Ca and hot flashes randomized to Venlafaxine 37.5-150mg/d vs. placebo, at 4wks, all active-tx groups had sig. greater symptomat improvement c/w placebo (Lancet 356:2059, 2000--AFP)
    2. Paroxetine 25mg/d was sig. more effective than placebo in a randomized trial in 165 postmenopausal women (JAMA 289:2827, 2003--abst)
    3. In a study in 150 symptomatic postmenopausal women 45-66yo randomized to receive placebo, fluoxetine, or citalopram x 9 months, there was no sig. diff. among the groups in frequency of hot flashes or an overall menopausal symptom index (Menopause 12:18, 2005--JW)
    4. In a study in 151 women (80% were breast Ca survivors) with troublesome hot flashes randomized to paroxetine 10-20mg/d vs. placebo x 4wks, then cross-over to other tx x 4wks, both dosages of paroxetine were associated with sig. improvements in hot flash frequency (with 20mg dose, mean reduction was 56% vs. 29% with placebo). (Clin. Oncol. 23:6919, 2005--JW)
    5. In a meta-analysis of 43 randomized trials of non-hormonal treatments for hot flashes (mostly < 12wks in duration), there were "modest" but sig. reduction of hot flashes with SSRIs; ditto for clonidine and gabapentin; no benefit for red clover isoflavone; mixed results for soy isoflavone extracts (JAMA 295:2057, 2006--JW)
    6. In a study in 205 perimenopausal or postmenopausal women 40-62yo with bothersome hot flashes or night sweats randomized to escitalopram 10mg QD (dose could be titrated to 20mg QD) vs. placebo x 8wks, the reduction in hot flash frequency from baseline was sig. greater in escitalopram group (from 9.8 to 5.3 w/escitalopram; from 9.8 to 6.4 w/placebo). (JAMA 305:267, 2011-JW)
  5. Gabapentin
    1. 59 postmenopausal women with hot flashes randomized to gabapentin 300mg TID vs. placebo.  After 12wks, hot flash frequency was reduced 45% with gabapentin and 29% with placebo (sig.) (Obs. Gyn. 101:337, 2003--abst)
    2. In a study in 60 menopausal women with moderate-to-severe hot flashes randomized to conjugated estrogens 0.625/d, gabapentin (titrated up to 2.4g/d over 12d) or placebo x 12wks; reduction in hot flash scores was 72% w/estrogen, 71% w/gabapentin, and 54% w/placebo.  Both active-tx groups had sig. greater improvements than placebo group.  (Obs. Gyn. 108:41, 2006--JW)
    3. See above re: 2006 JAMA meta-analysis
  6. Acupuncture for menopausal symptoms
    1. In a study in 248 postmenopausal women with hot flashes randomized to acupuncture vs. no acupuncture x 12wks, the acupuncture recipients had sig. greater reductions in both frequency and intensity of hot flashes, as well as somatic symptoms and sleep quality (Menopause 16:484, 2009-JW)
  7. Botanical/dietary treatments for menopausal symptoms
    1. MF101 (a combination of 22 Chinese herbs, has some effects on estrogen receptor-beta pathways)
      1. In a study in 217 menopausal women randomized to MF101 10g/d vs. placebo, the MF101 recipients had sig. greater median decrease in hot flash frequency (48% vs. 37%); MF101 group did have slight increases in endometrial thickness (Menopause 16:458, 2009-JW)
    2. Dong Quai--A traditional Chinese herb.
      1. 71 postmenopausal (> 6mos since last menses) women who had sx of either hot flashes or night sweats were randomized to dong quai root 4.5g TID vs. placebo x 6mos. At end of study period there was no diff. between the 2 groups in endometrial thickness (assessed by u/s), maturation of vaginal epithelial cells on cytologic evaluation, serum levels of estrodial, estrone, or serum hormone-binding globulin, or symptoms ("Kupperman index" or frequency of vasomotor episodes) (Fertil. Steril. 68:981, 1997--AFP)
    1. Soy products
      1. Soybeans contain isoflavones, which have some estrogen-like activity; tofu contains less than whole soybeans
      2. One randomized trial of 104 postmenopausal women showed increased reductions in frequency of hot flashes with soy protein supplements than with placebo (Obs. Gyn. 91:6, 1998--Med. Lett.)
      3. 51 perimenopausal women 45-55yo randomized to 20g/d of soy protein (containing 34mg of phytoestrogens) vs. a placebo additive x 6wks. Soy pts had sig. lower total cholesterol and LDL (by 5-7%) and diastolic BP (by 5mm Hg) and sig. decreased severity--but not frequency--of hot flashes (Menopause 6:7, 1999--JW)
      4. In a randomized trial of soy protein (150mg QD) + soy isoflavones (100mg QD) vs. soy protein alone vs. placebo in 80 menopausal women, over 4mos, isoflavone recipients had decreased menopausal sx (per Kupperman index) and decreased total and LDL-cholesterol; soy-protein-alone group had no change c/w placebo (Obs. Gyn. 99:389, 2002--JW)
      5. In a randomized 6mo crossover study of 62 postmenopausal women with hot flashes randomized to phytoestrogens (isoflavonoids, 114 mg/day) vs. placebo, there was no sig. diff. in hot-flash scores or mood indices between the two groups (Obs. Gyn. 101:1213, 2003--JW)
      6. In a study of 175 postmenopausal women (60-75yo) randomized to soy protein 25.6g/d vs. placebo x 1y, no sig. diff. at 1y in cognitive function, BMD, or plasma lipid levels (JAMA 292:65, 2004--JW)
      7. In a study in 202 postmenopausal women 60-75yo randomized to soy protein 36.5 g QD milk protein 36.5g QD x 1y, there was no sig. diff. in standardized ratings of health status (Menopause 12:56, 2005--JW)
      8. See above re: 2006 JAMA meta-analysis
    1. Black Cohosh (Cimicifuga racemosa) root
      1. Contains triterpenoid glycosides and isoflavones, both thought to have some estrogenic activity
      2. In a study in 301 women 45-70yo with at least 3mos of menopause-related symptoms randomized to black cohosh 7.5mg BID x 8wks (along with St. John's Wort 140mg BID) followed by half the dose x 8wks, vs. placebo, the active-tx group had sig. greater decreases on menopause sx scores and depression scores (Obs. Gyn. 107:247, 2006--JW) 
      3. In a study in 351 perimenopausal women 45-55yo with vasomotor sx randomized to black cohosh 160mg/d, multibotanicals (black cohosh, alfalfa, chaste tree, dong quai, and a number of others, multibotanicals + phone counseling to increase soy intake, HRT (combined unless s/p hysterectomy), vs. placebo. No sig. diff. between any treatment and placebo except for HRT in sx scores at 3mo, 6mo, and 12mos. (Ann. Int. Med. 145:869, 2006--JW)
    1. Red clover (Trifolium pratense) contains coumestrol, an isoflavone also found in soybean sprouts, with some estrogenic activity
      1. Ass'd with less decrease in bone mineral density than placebo in a 1y randomized trial of 107 peri- and post-menopausal women (abstract presented at Endocrine Soc. mtng 2000 per FP news 5/1/01 p. 24
      2. In a 12wk randomized placebo-controlled trial of 252 postmenopausal women having > 35 hot flashes/wk, users of neither of two red-clover-derived supplements (Promensil 82mg isoflavones/day or Rimostil 57mg isoflavones/day) had any sig. diff. in hot-flash counts than placebo recipients (JAMA 290:207, 2003--JW)
      3. See above re: 2006 JAMA meta-analysis
      4. No long-term safety data