Progesterone and Relief of Menopausal Symptoms

A number of hormonal changes occur as women enter menopause. The transition is characterized by erratic, but on average higher than premenopausal estrogen levels, while progesterone levels steadily decline as the number of menstrual cycles without ovulation increases, and remain extremely low thereafter.  Few researchers have studied the relationship between longitudinal changes in hormones and menopausal symptoms, although a recent study (see Randolph 2005 below) looked at levels of reproductive hormones and found only serum FSH (follicle-stimulating hormone) was associated with the frequency of hot flashes and night sweats.  Unfortunately the authors did not look at progesterone levels.  Menopausal symptoms are therefore not simply a sign of estrogen deficiency.

Progestins or progesterone have long been a component of postmenopausal hormone therapy, because they have been given to protect the uterus from the proliferative effects of estrogen that may otherwise lead to uterine cancer.  There is a great need for more studies of progesterone alone, without estrogen, in women with menopausal symptoms, since those that have been done have shown significant relief.  Dr. Jerilynn Prior is currently recruiting postmenopausal women for a study of micronized oral progesterone versus placebo, and examining its effects on vasomotor symptoms, forearm blood flow, lipid levels, and blood pressure in perimenopausal women experiencing vasomotor symptoms (www.clinicaltrials.gov identifier: NCT00152438).  Completion is expected in 2007.

• Randolph JF, Sowers MF, Bondarenko I, Gold EB, Greendale GA, Bromberger JT, Brockwell SE, Matthews K.  The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition.  J Clin Endocrinol Metab. 2005 Nov;90(11):6106-12.
  
  Vasomotor symptoms are experienced by 65-76% of women going through menopause.  This study examined longitudinal changes in estradiol, FSH, testosterone, DHEA, sex hormone binding globulin, free estrogen index and free testosterone index, and found that only FSH levels were associated with the prevalence and frequency of vasomotor symptoms.
  
  
• Stephenson K, Price C, Kurdowska A, Neuenschwander P, Stephenson J, Pinson B,  Stephenson D, Alfred D, Krupa A, Mahoney D, Zava D, Bevan M.  Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women. Presented at the 46th Annual Meeting of the American Society of Hematology, San Diego, December 4-7, 2004.  Blood 2004; 104(11): Abstract 5318. 
  
  No change in any of the thrombotic or inflammatory markers studied (total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6) was observed, despite significant relief of vasomotor symptoms compared to placebo, in 30 postmenopausal women receiving 20 mg/day progesterone cream for 4 weeks.  From this study the authors conclude that administration of topical progesterone cream at a daily dose of 20 mg significantly relieves menopausal symptoms in postmenopausal women without adversely altering prothrombotic potential. Since the thrombotic complications that are typically observed with conventional hormone replacement therapy, and have led to an increase in stroke,  do not seem to occur with topical progesterone, this treatment should be seriously considered as an effective and safe alternative clinical therapy for women suffering from menopausal symptoms.
  
  
• Montplaisir J, Lorrain J, Denesle R, Petit D. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause 2001; 8(1):10-16.
  
  This randomized clinical trial compared the effects of conjugated equine estrogen (CEE) and medroxyprogesterone acetate to CEE and oral micronized progesterone. Twenty-one postmenopausal women were studied in a sleep lab, with results demonstrating an improvement in subjective measures of menopausal symptoms and sleep in both groups. The group receiving natural progesterone had significantly improved sleep efficiency, whereas the medroxyprogesterone acetate group did not, suggesting that the former might better improve sleep in postmenopausal women.
  
  
• Ryan N, Rosner A. Quality of life (QOL) and costs associated with micronized progesterone and medroxyprogesterone acetate in hormone replacement therapy for non-hysterectomized, postmenopausal women. Clin Ther 2001 Jul;23(7):1099-115.
  
  This prospective, multicenter, randomized, parallel-group study enrolled 182 postmenopausal women 45 to 65 years of age and evaluated the quality of life and menopausal symptoms associated with the use of medroxyprogesterone acetate vs oral micronized progesterone when used as a part of a regular hormone replacement therapy. Menopausal symptoms improved in both groups from baseline to 9 months, as did QOL measures. In addition, patients using micronized progesterone had specific improvements in the areas of cognition and menstrual problems whereas the patients using MPA did not. Micronized progesterone was seen as an effective, cost-comparable alternative to MPA as well as being better tolerated.
  
  
• Fitzpatrick LA, Pace C, Wiita B. Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Women Health Gend Based Med 2000 May;9(4):381-7.
  
  A cross-sectional survey was conducted to examine quality of life (QOL) related to physiological, somatic, and vasomotor effects of switching progestogen treatment from medroxyprogesterone acetate (MPA) to micronized progesterone in postmenopausal women already using hormone replacement therapy (HRT). One hundred seventy-six women who were currently using hormone replacement therapy (HRT) containing micronized progesterone for 1-6 months and had previously received HRT containing MPA were surveyed to assess QOL. Women using micronized progesterone-containing HRT experienced significant improvement in vasomotor symptoms, anxiety, somatic complaints and depressive symptoms. Women reported improved control of menopausal symptoms and perceptions of their vaginal bleeding patterns while on the micronized progesterone-containing regimen. Approximately 80% of women reported satisfaction with the progesterone-containing therapy. A micronized progesterone-containing HRT therapy offers the potential for improved QOL with respect to menopausal symptoms.
  
  
• Leonetti HB, Longo S, Anasti JN. Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss. Obstet Gynecol 1999 Aug;94(2):225-8.
  
  In this randomized controlled trial, 102 menopausal women were treated with topical progesterone (Pro-gest®, 20 mg daily) or placebo and monitored for 1 year. Improvement in vasomotor symptoms was seen in 83% of the women in the treatment group who had experienced hot flashes, compared to 19% in the placebo group (p< .001). There was no difference noted in bone mineral densities between groups after one year. All women studied received a daily multivitamin and 1200 mg calcium.
  
  
• Wetzel W. Micronized progesterone: a new option for women's health care. Nurse Pract 1999 May;24(5):62-6, 71, 75-6.
  
  This paper discusses the use of micronized progesterone as a safe, effective, and well-tolerated therapy and reviews indications for use. It also includes case studies and issues of patient compliance and the need for an individualized treatment plan for women receiving hormone therapy.
  
  
• Sherwin BB. Progestogens used in menopause. Side effects, mood and quality of life. J Reprod Med 1999 Feb;44(2 Suppl):227-32.
  
  This review summarizes the effects of progesterone on mood and other brain functions. Progesterone receptors are present in many of the same areas of the brain as estrogen receptors, including the limbic system and hypothalamus. The limbic system plays a prominent role in regulating mood and emotion. As a comparison, progesterone decreases brain excitability, while estrogens increase it. This relates to why women with epilepsy have a higher frequency of seizures during the part of the cycle when estrogen levels are high, and a reduced frequency when progesterone levels are high. Estrogen and progesterone may also have differing effects on MAO, thereby affecting concentration of serotonin (a mood elevator) in the brain.
  
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