Hot, Confused and Cranky: A Novel Approach to Menopause
Thinning hair, painful joints,lost libido, vaginal dryness, hot flashes, night sweats, moodiness, crushing fatigue, difficulty concentrating, weight gain, itchy skin, incontinence…the list of symptoms during menopause is staggering. Staggering, but not surprising, since our cells are studded with receptors for hormones.
Vasomotor symptoms (hot flashes, night sweats), vaginal dryness, and dyspareunia (painful intercourse) are the main reason that women seek medical treatment. Over three-quarters of women report hot flashes within the 2 years surrounding menopause. A quarter suffer these symptoms for over five years, while an unfortunate ten percent of women report that they suffer from these symptoms for over ten years.1
For many physicians, hormone replacement therapy (HRT) is the preferred treatment strategy. However, research has shown that there may be risks associated with HRT, especially when given for more than five years. In 2002, the Women’s Health Initiative (WHI) conducted the largest, most rigorous study to date on hormone therapy, and found that HRT can increase the risk of both breast cancer and heart disease in healthy postmenopausal women.2 The study lasted five years and included 16,000 women. Follow-ups were published over the next two years looking at specific risks, such as stroke or heart disease, and then in 2008, WHI investigators looked at risk three years after stopping HRT, and found that although cardiovascular risk returned to normal, there was still a greater incidence of malignancies.3
Phytoestrogen preparations based on hops (Humulus lupulus) are new, because its potent phytoestrogen, 8-PN, was first identified in 1999. Hops extract with a standardized amount of 8-PN is effective in treating menopausal symptoms.
Even some famed traditional remedies haven’t panned out as hoped. In 2006, 351 women aged 45 to 55 were given a variety of botanicals or HRT, in a study called Herbal Alternatives for Menopause (HALT). One group received black cohosh (Cimicifuga racemosa); a second group received a multi-botanical consisting of black cohosh, alfalfa, boron, chaste tree, dong quai, false unicorn, licorice, oats, pomegranate and Eleutherococcus senticosus; a third group received the multi-botanical plus dietary counseling to increase the consumption of soy-based foods; a fourth group received estrogen, with or without progestin (HRT). Finally, a fifth group received placebo. After one year, all groups except those on HRT had no fewer hot flashes or night sweats.4 Only HRT gave significant relief.
At the time of the study, Ruth Kirschenstein, MD, acting director of one of the funding sponsors, the National Center for Complementary and Alternative Medicine (NCCAM), gave a prescient summary of the study’s surprising, disappointing results: “It highlights the importance of studying herbs using well-designed research to find out what works and what does not. With this information, women and their physicians can have a meaningful discussion of complementary and alternative medicine approaches to menopause.”5
About two million women turn 50 every year. The average age of onset for perimenopause is 47, with the average duration 3-4 years; 51 is the average age of menopause. For the many millions of women in menopause, and their physicians, we initiate that meaningful discussion by reviewing impressive new research, including human trials, on herbs and molecules that have proven benefit in ameliorating menopausal discomforts.
Prenylflavanoids: Potent, Proven Phytoestrogens
Prenylflavanoids are potent phytoestrogens present in the climbing vine known as hops (Humulus lupulus).6 They include xanthohumol (XN), isoxanthohumol (IX), and the extremely potent 8-prenylnaringenin (8-PN), one of our most active dietary phytoestrogens. Phytoestrogen preparations based on hops are fairly new, because 8-PN was first identified in 1999.7 It is a unique plant hormone that directly binds to ER alpha, one of the two human nuclear estrogen receptors. A nuclear receptor resides within a cell and can directly bind to DNA and regulate expression of nearby genes.
Then, in 2005, it was discovered that IX can be metabolized into 8-PN.8 In fact, IX is about ten times more prevalent in hops than 8-PN, and the conversion of IX to 8-PN depends both on an individual’s genes and the composition of bacteria in their gut. That means that hormonal response to hops can vary in intensity among individuals, depending on how much IX they convert to 8-PN. In one study of menopausal women, 35% were high or moderate converters of IX to 8-PN, while 65% were weak or non-converters.9
In a year long study, 57% of women taking a blend of three Asian herbs felt relief from perturbing menopausal symptoms within three months. Only 17% of the control group had relief.
Hops has proven effects in animal studies, such as reduction in tail-skin temperature and protection against bone loss in animals whose ovaries have been removed (considered a model for human hot flashes).10,11
Not surprisingly, given this remarkable confluence of active phytoestrogens, hops extract with a standardized amount of 8-PN is effective in treating menopausal symptoms. In a 2006 double-blind, placebo-controlled study, 67 menopausal women were given hops extract for 12 weeks. The extract contained a standardized amount of 8PN, either 100 or 250 µg. After six weeks, the 100 µg dose was significantly more effective than placebo at reducing hot flashes.12
A follow-up double-blind, placebo-controlled crossover study in 2010 also proved efficacy of hops, standardized to the 100 µg dose that was found effective in the first study. Here, 36 menopausal women were followed for 16 weeks. The women were randomly allocated to either placebo or hops for eight weeks, and then crossed over to the other treatment for another eight weeks. Symptoms were assessed by several widely used scales, after eight weeks, and after sixteen weeks. For the first eight weeks, all women improved but by sixteen weeks, only active treatment after placebo gave significant improvement. In contrast, women who took placebo after active treatment had an initial improvement, and then worsening of symptoms.13 The researchers note that a washout period was not used when switching between hops and placebo, because previous data suggest that washout is relatively rapid.14 The researchers conclude that, “Significant reductions in menopausal complaints for the active treatment in comparison with placebo were observed after 16 weeks, suggesting that the standardized hops extract is superior to placebo with respect to its potency to reduce menopausal complaints. Although the observed effects still need to be confirmed in further studies, phytoestrogen preparations containing this standardized hops extract may provide an interesting alternative to women seeking relief of mild vasomotor symptoms.”
Ancient Asian Folk Remedies Prove Effective in New Human Trials
Chinese herbs have been used and documented for hundreds if not thousands of common conditions, and menopause is no exception. Three popular herbal extracts have recently been tested in both laboratory and human studies, and been proven effective: Cynanchum wilfordii, Phlomis umbrosa, and Angelica gigas Nakai. The first, Cynanchum wilfordii, has been used for centuries as a traditional herbal treatment and is classified as a raw material for food by Korean Food and Drug Administration.15 C. wilfordii has been shown to improve epithelial function, protect liver cells, and protect cortical neurons.16,17,18 Phlomis umbrosa has been shown to inhibit mast cell secretions and histamine. It has been in use for nearly 400 years, and is a popular remedy taken after childbirth.19
In a 2008 animal study, ovariectomized animals showed significant improvement in bone mass density when treated with a combination of the three above extracts for 12 weeks.20 Human trials have also shown impressive results, increasing bone mass while relieving menopausal symptoms. In 2005, a prospective randomized clinical trial was performed on 48 perimenopausal women who visited Samsung Cheil hospital. Half were given a placebo and half were given a combination of the three extracts twice a day for twelve months. Bone mass density, serum bone markers, weight, body mass index, serum lipid profile, human growth hormone, follicle stimulating hormone (FSH) and estrogen were measured at the beginning of the trial and at 3, 6, 9 and 12 months.21 Hormones are measured because during perimenopause estrogen levels fluctuate and FSH remains elevated. By the time full blown menopause hits, estrogen and FSH are both low.
In the group taking the herbal extract, there was significantly improved bone density in the femur, higher blood levels of human growth hormone, and improved levels of triglycerides, compared to the control group. This is particularly notable because regular hormone replacement therapy (HRT) often increases triglycerides. Total cholesterol, body mass index, blood levels of estrogen and follicle stimulating hormone remained unchanged in both groups. Low density and high density lipoprotein (LDL and HDL) also remained unchanged in both groups. Again, HRT often leads to changes in these markers.
Unpleasant symptoms of menopause were markedly improved in the treatment group. A remarkable 57% of the study group felt relief from perturbing symptoms such as hot flashes, dyspareunia, sleep disorders, and fatigue by three months, while slightly less than 17% of the control group had relief.21
In a 2011 follow-up study, the same blend of three extracts was studied on 64 pre-, peri-and post-menopausal women. The Phase II double-blind, placebo-controlled safety study recruited patients from two medical practices in California and lasted for three months. Women were carefully selected, and were not allowed to participate if they had a suspicion of breast or endometrial malignancy, a personal or family history of breast cancer, a history of using estrogen or progestin-containing products in the prior 3 months, or other ailments such as uncontrolled hypertension, drug use, excessive weight or diabetes.22
Changes in the Kupperman menopause index (KMI), vaginal dryness, insomnia, nervousness, vertigo, and fatigue were all measured. The mean KMI score was significantly reduced in the group receiving the herbal extract, the constitutional and vasomotor symptoms were significantly improved, and there was a statistically significant improvement in vaginal dryness. During this three month period, there was not any significant weight gain or other serious adverse effects.22 In fact, the authors note that, “There were no significant changes in body weight, BMI, serum E2 (estradiol) levels, serum FSH levels, or liver enzymes, all of which have previously been observed with hormone replacement therapy.”22
A 2014 study of 96 menopausal women aged 40 to 60 found that a high dose of grape seed extract led to significant improvements in physical symptoms.
Finally, in a third, twelve week, phase III double-blind placebo controlled clinical study, which is yet to be published, 70 women aged 40-70 with menopausal symptoms were evaluated for twelve weeks. As with the previous 12-week study, the KMI score significantly improved, including many uncomfortable symptoms of menopause. The researchers conclude, “It is notable that this multi-center clinical study observed the significant improvement in quality of life…including hot flush, paresthesia, insomnia, nervousness, melancholia, vertigo, fatigue, joint or muscle pain, formication and vaginal dryness.”23 In the research on some other phytoestrogens, adverse effects have been monitored for up to five years.24,25 In this study, no negative side effects were observed, and although long-term follow-up will ultimately be definitive, this short-term research suggests effectiveness, tolerance and safety.
Effective Non-Hormonal Solutions to Menopausal Symptoms
Most approaches to menopause rely on tweaking hormonal balance—whether through conventional HRT, bioidentical HRT, or botanical medicines. However, other approaches can also be quite helpful, according to a 2008 review in the Cleveland Clinic Journal of Medicine. The authors, Marjorie Jenkins, MD, of Texas Tech University Health Sciences Center, and Andrea Sikon, MD, FACP, of Cleveland Clinic, note that “various nonhormonal options are available for treating menopausal symptoms.”1 The rationale for a nonhormonal approach is that the debilitating vasomotor symptoms of menopause, though initially triggered by falling estrogen levels, alter neurotransmitters such as serotonin and norepinephrine. That is why conventional medicine also offers selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Anticonvulsants such as gabapentin have also been used.
Succinic acid is a key biochemical intermediate which plays a role in the citric acid cycle, a part of the cellular energy-producing cycle. Although a preliminary clinical study on a succinate-containing product and menopause cannot be considered reliable because of incomplete reporting,26 a small number of very positive recent reports from menopausal women using succinate suggests that further research is warranted.
Magnesium is well known for its ability to ease insomnia, muscle cramps and spasms, irritability, migraines and more.27 Magnesium levels tend to decrease during menopause. Inadequate magnesium appears to reduce serotonin levels, and antidepressants have been shown to raise brain magnesium.28 Magnesium supplementation has been shown to slow bone turnover in postmenopausal women suffering from osteoporosis.29
Another non-hormonal and effective treatment is pure, uncontaminated grape seed extract. A 2014 study of 96 menopausal women aged 40 to 60 received either placebo, or grape seed extract in low dose (100 mg/day) or high dose (200 mg/day). The study was randomized, double-blind, and lasted eight weeks. In the high dose group, there were significant improvements in physical symptoms, hot flashes, insomnia, anxiety, and depression. In both the low dose and high dose groups, blood pressure decreased and muscle mass increased.30
Grape seed extract contains a potent class of polyphenol antioxidants known as proanthocyanidins, which do not bind to estrogen receptors. These antioxidants have been studied for their analgesic, anti-inflammatory and heart-protective abilities. One proanthocyanidins-rich pine bark extract was found to alleviate menopausal symptoms.31 Grape seed may prove even more effective, since the proanthocyanidins extracted from grape seed have a higher molecular weight than those extracted from pine bark.32 That may be why, unlike pine bark, 200 milligrams daily of grape seed extract led to ”remarkable improvement…in…anxiety. The HADS-Anxiety subscale score decreased in both the high-dose and the low-dose GSPE groups as early as 4 weeks after treatment initiation.”30
Grape seed extract is well known for its ability to lower blood pressure and reduce heart rate.33 This study confirmed the extract’s heart-protective effects: “The mean systolic and diastolic blood pressure decreased by approximately 5 mm Hg in both the low-dose and the high-dose groups after 8 weeks of treatment. This effective reduction in blood pressure with GSPE treatment may suggest the high bioactivity of the polyphenol antioxidant used.”30 In addition, atherosclerotic lesions in the aorta of rabbits fed a high cholesterol diet were significantly reduced by adding grape seed extract—more so than green tea extract.34
A unique blend of safety and efficacy is the golden mean every good physician tries to reach. For the millions of women suffering from disturbing menopausal symptoms, women searching for gentle ways to recalibrate their changing bodies, there are increasingly good options.
- Jenkins MR, Sikon AL. Update on nonhormonal approaches to menopausal management. Cleve Clin J Med. 2008 May;75 Suppl 4:S17-24. PMID: 18697262 View Abstract
- Women’s Health Initiative Investigators. 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. PMID: 12117397 View Abstract
- WHI Investigators. Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin. JAMA. 2008;299(9):1036-1045. PMID: 18319414 View Abstract
- Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006 Dec 19;145(12):869-79. PMID: 17179056 View Abstract
- Miyamoto M, Matsushita Y, Kiyokawa A et al. Prenylflavonoids: a new class of non-steroidal phytoestrogen (Part 2). Estrogenic effects of 8-isopentenylnaringenin on bone metabolism. Planta Med 1998;64. PMID: 9741296 View Abstract
- Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops (Humulus lupulus L.) and beer. J Clin Endocrinol Metab. 1999 Jun;84(6):2249-52. PMID: 10372741 View Abstract
- Possemiers S, Heyerick A, Robbens V, De Keukeleire D, Verstraete W. Activation of proestrogens from hops (Humulus lupulus L.) by intestinal microbiota; conversion of isoxanthohumol into 8-prenylnaringenin. J Agric Food Chem. 2005 Aug 10;53(16):6281-8. PMID: 16076107 View Abstract
- Bolca S, Possemiers S, Maervoet V, Huybrechts I, Heyerick A, Vervarcke S, Depypere H, De Keukeleire D, Bracke M, De Henauw S, Verstraete W, Van de Wiele T. Microbial and dietary factors associated with the 8-prenylnaringenin producer phenotype: a dietary intervention trial with fifty healthy post-menopausal Caucasian women. Br J Nutr. 2007 Nov;98(5):950-9. Epub 2007 May 23. PMID: 17521469 View Abstract
- Bowe J, Li XF, Kinsey-Jones J, Heyerick A, Brain S, Milligan S, O’Byrne K. The hop phytoestrogen, 8-prenylnaringenin, reverses the ovariectomy-induced rise in skin temperature in an animal model of menopausal hot flushes. J Endocrinol. 2006 Nov;191(2):399-405. PMID: 17088409 View Abstract
- Hümpel M, Isaksson P, Schaefer O, Kaufmann U, Ciana P, Maggi A, Schleuning WD. Tissue specificity of 8-prenylnaringenin: protection from ovariectomy induced bone loss with minimal trophic effects on the uterus. J Steroid Biochem Mol Biol. 2005 Nov;97(3):299-305. Epub 2005 Sep 8. PMID: 16153822 View Abstract
- Heyerick A, Vervarcke S, Depypere H, Bracke M, De Keukeleire D. first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 54 (2006) 164–175. PMID: 16321485 View Abstract
- Erkkola R, Vervarcke S, Vansteelandt S, Rompotti P, De Keukeleire D, Heyerick A. 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. PMID: 20167461 View Abstract
- Rad M, Hümpel M, Schaefer O, Schoemaker RC, Schleuning WD, Cohen AF, Burggraaf J. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women. Br J Clin Pharmacol. 2006 Sep;62(3):288-96. PMID: 16934044 View Abstract
- Personal communication with 3Herbal Hormone Research Institute, Naturalendo Tech Co, Seoul, Korea
- Choi DH, Lee YJ, Oh HC, Cui YL, Kim JS, Kang DG, Lee HS. Improved endothelial dysfunction by Cynanchum wilfordii in apolipoprotein E(-/-) mice fed a high fat/cholesterol diet. J Med Food. 2012 Feb;15(2):169-79. PMID: 22082065 View Abstract
- Lee MK, Yeo H, Kim J, Kim YC. Protection of rat hepatocytes exposed to CCl4 in-vitro by cynandione A, a biacetophenone from Cynanchum wilfordii. J Pharm Pharmacol. 2000 Mar;52(3):341-5. PMID: 10757424. View Abstract
- Lee MK, Yeo H, Kim J, Markelonis GJ, Oh TH, Kim YC. Cynandione A from Cynanchum wilfordii protects cultured cortical neurons from toxicity induced by H2O2, L-glutamate, and kainate. J Neurosci Res. 2000 Jan 15;59(2):259-64. PMID: 10650884 View Abstract
- Shin TY, Kim SH, Kim DK, Leem KH, Park JS. Phlomis umbrosa root inhibits mast cell-dependent allergic reactions and inflammatory cytokine secretion. Phytother Res. 2008 Feb;22(2):153-8. PMID: 18167054 View Abstract
- Nam-Jin L, Geun-Soo K, Bo-Yeon K, Kwon-Taek Y, Jae-Kyung L, Yu-Ri J, Chun Mei L, Jae Soo K, Jong-Goo K. Anti-postmenopausal Effect of the Newly-Developed Phytoestrogen, FGF271, in Vitro and in Vivo Lab. Anim. Res. 2008: 24(2), 167-172.
- Ki Ho L, , Duck Joo L, Sang Man K, Sang Hyeun J, Eun Ki K, Hae Seung H, In Kwon H. Evaluation of Effectiveness and Safety of Natural Plants Extract (Estromon®) on Perimenopausal Women for 1 Year. J. of Korea Society of Menopause Vol. 11 No.1 March 2005
- Chang A, Kwak BY, Kwontaek Y, Jae SK. The Effect of Herbal Extract (EstroG-100) on Pre-, Peri- and Post-Menopausal Women: A Randomized Double-blind, Placebo-controlled Study. Phytother. Res. 26: 510–516 (2012). PMID: 21887807 View Abstract
- Duck-Joo L, Seok-Kyo S. The Evaluation of the Efficacy and Safety of Herbal Extract (PAC-EX01: EstroG-100) on Menopausal Symptoms: 12 weeks, Multi Center, A randomized, Double Blind Placebo-Controlled Clinical Study.
- Alexandersen P, Toussaint A, Christiansen C, Devogelaer JP, Roux C, Fechtenbaum J, Gennari C, Reginster JY. Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. JAMA. 2001 Mar 21;285(11):1482-8. PMID: 11255425 View Abstract
- Unfer V, Casini ML, Costabile L, Mignosa M, Gerli S, Di Renzo GC. Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril. 2004 Jul;82(1):145-8. PMID: 15237003 View Abstract
- Peskov AB, Maevskii EI, Uchitel ML, et al. Succinate-based preparation alleviates manifestations of the climacteric syndrome in women. Bull Exp Biol Med 2005;140:312-4. PMID: 16307045 View Abstract
- S. Johnson. 2001. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses 56(2): 163-70. PMID: 11425281 View Abstract
- Aydin H, Deyneli O, Yavuz D, Gözü H, Mutlu N, Kaygusuz I, Akalin S. Short-Term Oral Magnesium Supplementation Suppresses Bone Turnover in Postmenopausal Osteoporotic Women. Biol Trace Elem Res. 2010 Feb;133(2):136-43. PMID: 19488681 View Abstract
- Terauchi M, Horiguchi N, Kajiyama A, Akiyoshi M, Owa Y, Kato K, Kubota T. 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. PMID: 24518152 View Abstract
- Yang HM, Liao MF, Zhu SY, Liao MN, Rohdewald P. A randomised, double-blind, placebo-controlled trial on the effect of Pycnogenol on the climacteric syndrome in peri-menopausal women. Acta Obstet Gynecol Scand 2007;86:978-985. PMID: 17653885 View Abstract
- Weber HA, Hodges AE, Guthrie JR, et al. Comparison of proanthocyanidins in commercial antioxidants: grape seed and pine bark extracts. J Agric Food Chem 2007;55:148-156. PMID: 17199326 View Abstract
- Feringa HH, Laskey DA, Dickson JE, Coleman CI. The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc 2011;111:1173-1181. PMID: 21802563 View Abstract
- 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. PMID: 9920515 View Abstract
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