Clinically Effective, Evidence-Based, Non HRT/BHRT Treatment Options for Perimenopause

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imagesThis article first appeared in the Townsend Letter: Dr. Todd A. Born is a naturopathic doctor, co-owner and medical director of Born Naturopathic Associates, Inc., in Alameda, California.  Dr. Born is the Product Manager, Head of New Product Development, Scientific Advisor for Allergy Research Group, LLC and is Editor in Chief of their science Focus Newsletter.  He is a Thought Leader for the UK-based Clinical Education, a free peer-to-peer service that offers clinicians a closed forum to ask clinical questions and receive evidence-based responses by experts in their fields.

As healthcare practitioners, we see the following scenario play out in our practice a few times a week: 48 year old female presents with chief concerns of hot flashes, night sweats, irritability, xerosis, dry eyes, vaginal atrophy, dyspareunia, sleep dysfunction, mood swings, an irregular menstrual cycle and memory concerns.

You run some blood chemistries and everything is unremarkable besides decreasing estrogen and progesterone, with an increase in FSH. This woman clearly is in the throes of perimenopause. She’s hesitant to start hormone or biological hormone replacement therapy because of what she has heard and read online about side effects and risks of prolonged hormone replacement.

You begin to comb the rolodex of treatment options that actually work, have a very low side effect profile and minimal, if any long term risks, but you can’t think of any that work quite as well as hormones.

This article will discuss the definition of menopause, clinical signs and symptoms, long-term consequences of estrogen deficiency, conventional treatments and finally, evidence-based, non-hormonal approaches.

The average onset of perimenopause in the United States is at the age of 47.5 years. The average duration of perimenopause is 4 years, with the median age of 12 months of amenorrhea occurring at 51.4 years of age.[i] An article in February 2015 in JAMA, looking at 3302 women showed that vasomotor symptoms lasted for more than 7 years in more than half the women, and persisted for 4.5 years after the final menstrual period.[ii]

The most common symptoms women experience are hot flashes, night sweats, sleep disturbances, vaginal dryness and mood changes. Less common, but still prevalent, include recent onset depression, arthralgias, memory loss, breast pain and menstrual migraines.[iii]

The long-term consequences of estrogen deficiency include osteopenia/osteoporosis,[iv] dementia (but only in those that have artificially induced premature menopause)[v], dyslipidemia[vi],[vii] and cardiovascular diseases.[viii],[ix]

Although the evidence varies for the risks of prolonged (>5 years) use of hormone replacement therapy (HRT), at this time the preponderance of data indicates that HRT, particularly unopposed oestrogens, should not be used long term.[x] The risks and consequences include, endometrial hyperplasia, coronary heart disease (CHD), stroke, venous thromboembolism (VTE) and breast cancer.[xi],[xii]

There is a major misconception amongst many health care providers and the general public that bio-identical hormone replacement therapy (BHRT) is safer than HRT. Albeit this makes sense logically, particularly to integrative healthcare practitioners, in that one would want to use a hormone with the same molecular structure as a hormone that is endogenously produced, versus one that is completely synthetic, but both carry similar risk profiles, [xiii],[xiv],[xv],[xvi] except for medroxyprogesterone acetate (MPA). It is believed that MPA increases the risk of breast cancer,[xvii],[xviii] while this has not yet been seen in bio-identical use of progesterone.[xix]

More and more clinicians, as well as more and more patients, are looking into safe and effective alternatives as a first line intervention to alleviate menopausal symptoms. Let’s take a look at what natural agents have some of the strongest human efficacy, while also carrying a strong safety profile, even in the long term.

  • Patented extract from Humulus lupulus, high in prenylfavonoids, particularly 8-prenylnaringenin (8-PN).
    • A 2006 double-blind, randomized, placebo controlled trial in 67 menopausal women given the extract for 12 weeks significantly reduced hot flashes over placebo.[xx]
    • A 2010 double-blind, placebo-controlled crossover study in 36 menopausal women followed for 16 weeks showed improvement in most menopausal complaints.[xxi]
  • Combination of three Korean herbs: Cynanchum wilfordii, Phlomis umbrosa, and Angelica gigas
    • Human trials have shown increase in bone mass, while relieving menopausal symptoms.
      • In a 2005, prospective RCT, 48 perimenopausal women were given the extract twice a day, or placebo, for 12 months. By the end of the study, it was shown that the group that took the extract had improved bone density, increased human growth hormone and improved triglycerides. At the 3rd month mark, 57% reported improvements in hot flashes, dyspareunia, sleep disorders and fatigue. Only 17% of the control group reported improvements.[xxii]
      • A 2012, phase II double-blind, placebo-controlled safety study in 64 pre-, peri- and post-menopausal women followed for 12 weeks showed “the constituting symptoms of vasomotor, paresthesia, insomnia, nervousness, melancholia, vertigo, fatigue and rheumatic pain were significantly improved in the EstroG-100 group in comparison with the placebo group (p < 0.05). Statistically significant improvement in vaginal dryness in the EstroG-100 group was also observed compared with that of the placebo group (p < 0.05). In conclusion, EstroG-100 significantly improved the menopausal symptoms of pre-, peri- and post-menopausal women without weight gain or any serious side effects.”[xxiii]
  • Patented grape seed extract high in proanthocyanidins.
    • A 2014, randomized, double-blind, placebo-controlled pilot study enrolled 96 women aged 40-60, who had at least one menopausal symptom. They were given either 100 mg/day, 200 mg/day, or placebo for 8 weeks. It was shown that in the 200 mg/day group, hot flashes reduced, anxiety improved, systolic and diastolic blood pressures decreased, and in both 100 mg and 200 mg group, lean muscle mass increased.[xxiv]
    • Although not a human trial, in 1999, rabbits fed a high cholesterol diet and which developed atherosclerotic lesions, had these lesions significantly reduced when adding in the grape seed extract to their diets.[xxv]


The variability of what women will experience through the menopausal transition is vast, but given that most experience at least one of the aforementioned symptoms, with an average duration of 4 years, it makes sense that we have a duty as clinicians to alleviate their symptoms as much as possible, as safely and effectively as possible. One can see that this can be done without going straight to hormone replacement therapies, although this intervention may be needed for certain individuals.

We have a responsibility to use tools in our toolbox that work and have human data to support efficacy. Here, I have shown that these natural therapeutics do exist.


[i] McKinlay SM, Brambilla DJ, Posner JG. The normal menopause transition. Maturitas. 1992;14(2):103.

[ii] Avis NE, Crawford SL, Greendale G, et al. Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition. JAMA Intern Med. 2015 Feb 16.

[iii] Woods NF, Mitchell ES. Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women’s lives. Am J Med. 2005;118 Suppl 12B:14.

[iv] National Osteoporosis Foundation. What Women Need to Know. Accessed February 13, 2015.

[v] Henderson, Victor W. Cognitive Symptoms and Disorders in the Midlife Woman. The North American Menopause Society. Accessed February 13, 2015.

[vi] Derby CA, Crawford SL, Pasternak RC, et al. Lipid changes during the menopause transition in relation to age and weight: the Study of Women’s Health Across the Nation. Am J Epidemiol. 2009 Jun;169(11):1352-61. Epub 2009 Apr 8.

[vii] Woodard GA, Brooks MM, Barinas-Mitchell E, et al. Lipids, menopause, and early atherosclerosis in Study of Women’s Health Across the Nation Heart women. Menopause. 2011 Apr;18(4):376-84

[viii] American Heart Association. Menopause and Heart Disease. Accessed February 13, 2015.

[ix] Rosano GM, Vitale C, Marazzi G, et al.    Menopause and cardiovascular disease: the evidence. Climacteric. 2007 Feb;10 Suppl 1:19-24.

[x] Barrett-Connor E, Stuenkel CA. Hormone replacement therapy (HRT)–risks and benefits. Int J Epidemiol. 2001 Jun;30(3):423-6.

[xi] Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701.

[xii] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended post stopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013 Oct;310(13):1353-68.

[xiii] Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health (Larchmt). 2007;16(5):600.

[xiv] Bhavnani BR, Stanczyk FZ. Misconception and concerns about bioidentical hormones used for custom-compounded hormone therapy. J Clin Endocrinol Metab. 2012 Mar;97(3):756-9. Epub 2011 Dec 28.

[xv] FDA. Bio-Identicals: Sorting Myths from Facts. Accessed February 13, 2015.

[xvi] Unknown. Menopausal Hormone Therapy and Cancer Risk. February 2015. Accessed February 27, 2015.

[xvii] Prentice RL. Postmenopausal hormone therapy and the risks of coronary heart disease, breast cancer, and stroke. Semin Reprod Med. 2014 Nov;32(6):419-25.

[xviii] Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.

[xix] Moskowitz D. A comprehensive review of the safety and efficacy of bioidentical hormones for the management of menopause and related health risks. Altern Med Rev. 2006 Sep;11(3):208-23.

[xx] Heyerick A, Vervarcke S, Depypere H, et al. First prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas. 2006 May 20;54(2):164-75.

[xxi] Erkkola R, Vervarcke S, Vansteelandt S, et al. A randomized, double-blind, placebo-controlled, cross-over pilot study on the use of a standardized hop extract to alleviate menopausal discomforts. Phytomedicine. 2010 May;17(6):389-96

[xxii] Ki Ho L, Duck Joo L, Sang Man K, et al. Evaluation of Effectiveness and Safety of Natural Plants Extract (Estromon®) on Perimenopausal Women for 1 year. J. of Korea Society of Menopause. Vol 1, No. 1 March 2005.

[xxiii] Chang A, Kwak BY, Yi K, Kim JS. The effect of herbal extract (EstroG-100) on pre-, peri- and post-menopausal women: a randomized double-blind, placebo-controlled study. Phytother Res. 2012 Apr;26(4):510-6.

[xxiv] Terauchi M, Horiguchi N, Kajiyama A, et al. Effects of grape seed proanthocyanidin extract on menopausal symptoms, body composition, and cardiovascular parameters in middle-aged women: a randomized, double-blind, placebo-controlled pilot study. Menopause. 2014 Sep;21(9):990-6.

[xxv] Yamakoshi J, Kataoka S, Koga T, Ariga T. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 1999 Jan;142(1):139-49.



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