Regulating Hormones

Dr David Cannata

A normal menstrual cycle is reflective of hormonal harmony. While the ultimate goal of the female sex hormone balancing act is preparing for pregnancy, it is clear that it’s important for other pathways and systems that are influenced by these hormones. Premenstrual Syndrome (PMS) and symptoms of menopause are key examples of when the imbalance of hormones can disrupt other areas within the body such as neurotransmitter activity and vasomotor control.

PMS & Menopause

PMS involves a wide range of physical and psychological symptoms but exact causes remain unknown. Many symptoms of PMS are indicative of excess estrogen activity; however some reflect estrogen deficiency. When one menstrual cycle hormone is imbalanced it can impact the other menstrual cycle hormones, disrupting the overall cycle and pathways influenced by hormonal activity resulting in PMS symptoms. This places an emphasis on the ability to regulate hormones levels in the treatment/prevention of PMS and cycle irregularities.

The transition through to menopause can bring about an array of symptoms that can last for years and impair quality of life. The most disruptive symptom is hot flushes/night sweats. Menopausal symptoms are believed to arise from the withdrawal of estrogen. The decline of estrogen activity within the body has a significant impact because it is involved in the regulation of many pathways. These include emotional/psychological stability via interactions with neurotransmitters; and vasomotor control via interactions with other hormones and the hypothalamus-pituitary adrenal (HPA) axis. The opioid system, bone metabolism and melatonin secretion also interact with estrogen and are affected when estrogen declines. Thus in treating menopause, whilst similar principles to PMS apply, the main focus is regulating and supporting estrogen activity along with the interacting mechanisms that are influenced by estrogen withdrawal.

Two common treatment options involved in hormone regulation are chasteberry and isoflavones from soy. Chasteberry not only displays mechanisms to regulate several menstrual cycle hormones, but also properties that can support the pathways under estrogen influence. Studies on soy isoflavones are starting to break away from the umbrella term of phytoestrogens and are showing a real efficacy towards treating hot flushes. Here we take a closer look at these treatment options.

Chasteberry

Chasteberry is the fruit of the chaste tree (Vitexagnuscastus), a small shrub native to the Mediterranean and Central Asia regions. It has been used for thousands of years for female reproductive and menstrual problems. Its pharmacological effects appear to derive from the combination and synergistic behaviour of active constituents which include flavonoids, iridoid glycosides, volatile and essential oils and diterpenes. This unique combination of compounds has the ability to regulate hormone levels particularly in excessive or deficient hormonal states.
Several mechanisms have been discovered to explain some of the pharmacological benefits of chasteberry, but given the variety and combination of active constituents, it will take some time before a greater and more complete understanding of the therapeutic benefits of chasteberry are made. Diterpenes from chasteberry are known as D2 receptor agonists that can initiate a dopaminergic response that inhibits the over-production and -secretion of prolactin. This is particularly beneficial in cases of hyperprolactinemia which is a factor in fertility ovulatory disorders and irregular cycles. Hyperprolactinemia is also responsible for decreasing progesterone and estrogen levels so supplementation with chasteberrycan increase progesterone and estrogen whilst reducing prolactin. Importantly, chasteberry has shown it can leave prolactin levels unaffected when levels are normal [1] and iseven known for its use during breastfeeding to promote lactation by increasing prolactin. This highlights that chasteberry is a hormone regulator or balancer towards normalization rather than having specific mechanisms to only elevate or decrease hormone levels.

Chasteberry flavonoid apigenin has selective binding affinity for the β-estrogen receptor subtype (ERβ) whilst casticin and others,are agonists for μ- and δ-opioid receptors. By activating the opioid system, there are well established benefits towards providing pain relief and tolerance as well as the production and release of β-endorphins. However the opioid system directly and indirectly interacts with several menstrual hormones and plays a role in controlling mood, appetite, thermoregulation and hypothalamic-pituitary adrenal (HPA) axis activity. These additional roles indicate how chasteberry can have a therapeutic benefit for several PMS and menopausal symptoms.

Evidence

A review of 8 clinical randomized-controlled studies [2] revealed that chasteberry was effective in normalizing irregular cycles and relieving PMS and Premenstrual Dysphoric Disorder (PMDD) symptoms in 7 of the 8 trials compared to their respective controls. On average around 67% of irregular cycles returned to normal and symptoms were reduced ranging from 25-50%. A randomized, double-blind placebo-controlled study [3]demonstrated chasteberry was significantly superior to placebo at reducing many PMS symptoms in women with moderate to severe PMS (n = 67). This result was also replicated in a larger, multi-centre study (n = 217) [4].Another study illustrated that 20mg/d of Chasteberry extract (equiv. dry 200mg) was as effective as 30mg/d of Chasteberry and more effective than 8mg/d of Chasteberry and placebo at improving total symptom scores in women suffering from PMS [5].In a randomized, double-blind placebo controlled study involving 52 women with luteal phase defects, 20mg/d of chasteberry significantly reduced prolactin release, normalized luteal phases, improved luteal progesterone and estrogen levels [6]. Other studies have shown chasteberry supplementation can improve hormone levels, normalize cycles and improve pregnancy rate in women with a variety of ovulatory problems [1, 7-9].

Currently there is limited clinical data for chasteberry as a single ingredient in the treatment of menopausal symptoms despite key therapeutic mechanisms like increasing dopaminergic and opioid receptor activity being established. A survey of 276 herbalists in the UK revealed that majority (86.3%) prescribed chasteberry for the treatment of menopausal symptoms[10] and it is a common inclusion in multi-herbal formulations for menopause.

Soy Isoflavones

Genistin, diadzin and glycitin are isoflavones found in soy (Glycine max), also known as phytoestrogens; non-steriodal plant derived compounds which exert estrogen-like effects. Upon digestion, these isoflavones can be hydrolyzed by digestive enzymes and bacteria to be converted to their aglycone forms genistein, daidzein and glycitein, respectively. Around one third of the world population contains certain intestinal bacteria that further metabolize daidzein into S-equol. These aglyconeisoflavones are then able to be absorbed in the intestines and are responsible for the biological activities. Their structure is similar to 17β-estradiol as well as anti-estrogens, thus can compete with estrogen by binding to estrogen receptors and initiating transcriptional activity. Depending on the current endogenous estrogen levels of the body, genistein and daidzein can have agonistic or antagonistic effects, thereby can regulate or normalize activity in hypo- (menopause) or hyper- (PMS) estrogenic states. Genistein exerts mild estrogenic activity (around 35% of 17β-estradiol), so if estrogen levels are high, it will lower activity; if estrogen levels are low, it will increase (See Figure). The main focus has been for their ability to control climacteric hot flushes, but their mechanisms suggest they can regulate all symptoms related to estrogen fluctuations. Genistein is believed to have a greater binding affinity to estrogen receptors than daidzein, with a preference towards ERβ compared to estrogen receptor α (ERα). Like genistein, S-equol has a preference for ERβ, but is thought to have a higher overall affinity than genistein. Therefore efficacy as well as bioavailability of isoflavones is influenced by digestive health and the intestinal microflora which could be a factor into explaining individual variance in responsiveness to treatment.

estrogen_hormone

Figure: Basic diagram of soy isoflavones estrogenic mechanism. Soy isoflavones can normalize estrogen activity in both hyper- and hypo-estrogenic states. The mild estrogenic activity and preference for the β-estrogen receptor limit the possibility of serious side effects that are associated with HRT.

Evidence

Previously there was some confusion over efficacy, as previous meta-analytical reviews did not distinguish the different types of phytoestrogens; so lignans and various isoflavones from red clover, soy and other plant materials were grouped together. Red clover (Trifolium pretense) contains a variety of isoflavones with the most common being biochanin A and formonentin. They are 4’-O-methyl derivatives of genistein and daidzein, respectively. Their demethylation can be carried out by intestinal bacteria or hepatic enzymes, but this has a relatively low efficiency and establishes a key difference between isoflavones from soy and those from red clover.

Reviews that are specific for soy isoflavones have demonstrated efficacy in treating menopausal hot flushes. A meta-analysis of 17 randomized placebo-controlled trials (n = 1,992) [11] revealed that soy isoflavone supplementation (mean: 54mg/d soy isoflavones) significantly reduced hot flush frequency (by 20.6% (mean); P<0.0001) and severity (26.2%; P = 0.001) greater than placebo. Another review of 14 clinical studies revealed that when a dose of soy isoflavones was 50mg/d or higher, it could significantly reduce hot flushes [12].

In addition to the results of these large reviews, clinical studies have also shown soy isoflavones significantly reduce night sweats [13, 14] and improve lipid balance [15, 16] and quality of life (sexual, physical, psychosexual & vasomotor) [17] greater than placebo. Of most interest, soy isoflavones significantly reduced overall Kupperman Index scores (-44.2%) greater than placebo (+3.2%; P<0.01) indicating the benefits of soy isoflavones to improve all aspects of menopause/climacteric symptoms and not just vasomotor [15]. Currently only one quality study demonstrates that soy isoflavone supplementation can reduce PMS-related symptoms such as headache, breast tenderness, cramps and swelling[18]. The greater focus of soy isoflavones on hot flushes as opposed to other climacteric symptoms and PMS is because it is the most common symptom that women will seek treatment for due to its ability to reduce quality of life. Soy isoflavones have great potential to improve these other symptoms, but it is the ability to provide relief from hot flushes that is most desired and therefore researched.

References

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    Kombinationsarzneimittel.’ Der Kassenarzt. 7: p. 51–60.
  2. van Die, M.D. et al., (2013) ‘Vitex agnus-castus extracts for female reproductive disorders: a systematic review of clinical trials.’ Planta Med. 79(7): p. 562-75.
  3. Ma, L. et al., (2010) ‘Treatment of moderate to severe premenstrual syndrome with Vitex agnus castus (BNO 1095) in Chinese women.’ Gynecol Endocrinol. 26(8): p. 612-6.
  4. He, Z. et al., (2009) ‘Treatment for premenstrual syndrome with Vitex agnus castus: A prospective, randomized, multi-center placebo controlled study in China.’ Maturitas. 63(1): p. 99-103.
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  7. Bergmann, J. et al., (2000) ‘[The efficacy of the complex medication Phyto-Hypophyson L in female, hormone-related sterility. A randomized, placebo-controlled clinical double-blind study].’ Forsch Komplementarmed Klass Naturheilkd. 7(4): p. 190-9.
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  12. (2011) ‘The role of soy isoflavones in menopausal health: report of The North American Menopause Society/Wulf H. Utian Translational Science Symposium in Chicago, IL (October 2010).’ Menopause. 18(7): p. 732-53.
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  14. Upmalis, D.H. et al., (2000) ‘Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study.’ Menopause. 7(4): p. 236-42.
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  16. Petri Nahas, E. et al., (2004) ‘Benefits of soy germ isoflavones in postmenopausal women with contraindication for conventional hormone replacement therapy.’ Maturitas. 48(4): p. 372-80.
  17. Basaria, S. et al., (2009) ‘Effect of high-dose isoflavones on cognition, quality of life, androgens, and lipoprotein in post-menopausal women.’ J Endocrinol Invest. 32(2): p. 150-5.
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