Perimenopause and Menopause Naturopathic Protocol

Perimenopause and Menopause Naturopathic Protocol

This Perimenopause and Menopause Naturopathic Protocol is provided as information for patients of HealthMasters Naturopath Kevin Tresize ND as part of a treatment plan to assist patients with understanding of their treatment plan and should not be substituted for medical advice, diagnosis or treatment. It is important to note that this is a summary only and is intended to assist discussion between practitioner and patient as part of consultations. This Perimenopause and Menopause Naturopathic Protocol may be changed to suit the individual requirements of the patient and should not be substituted for medical advice, diagnosis or treatment.

HealthMasters Naturopath Kevin Tresize ND

 

Overview:

1. Pathophysiology

2. Consultation Overview

3. Key Drivers

4. Treatment Priorities

5. Red Flags

6. Treatment Recommendations

7. Supportive Programs

8. Diet and Lifestyle Recommendations

9. Clinical Investigation and Pathology

10. Pharmaceutical Treatments

11. Additional Resources

12. Footnotes

13. References



1. Pathophysiology

  • Perimenopause is the interval preceding menopause,[1] which marks the end of female reproductive ability characterised by the natural decline of ovarian function.[2]
  • This leads to shifts in the hormonal environment driven by the depletion of ovarian follicles, referred to as gametogenic ovarian failure.[3],[4]
  • As the functional capacity of ovarian follicles decreases, signalling hormones and markers produced by ovarian granulosa cells also decline, including antimüllerian hormone (AMH) and inhibin B levels. These provide feedback control that suppress pituitary hormone, follicle stimulating hormone (FSH).
  • In response to these events, the hypothalamus triggers a surge in the release of gonadotrophin-releasing hormone (GnRH).[5] This is followed by a 10 to 15-fold increase in FSH and luteinising hormone (LH); which promote ovarian folliculogenesis and oestradiol secretion.[6] 
  • The combined effects of these changes result in erratic fluctuations in oestradiol levels. However, over time, the continued decline of ovarian follicles eventually leads to the permanent reduction of oestradiol and progesterone production.[7],[8],[9],[10]
  • Collectively, over several months to years, these hormonal changes disrupt the process of ovulation. This in turn causes changes to menstrual cycle length, frequency and regularity during the perimenopausal phase, until the cessation of menses.[11]
  • Beyond irregular menstrual cycles, perimenopausal hormonal changes are associated with a range of symptoms including hot flushes, vaginal dryness and low libido.[12] These can vary in their impact, ranging from no symptoms to severe symptoms that diminish quality of life.[13],[14] Table 1 outlines median age, phases and features of the menopausal transition.
  • Further, the loss of oestradiol and progesterone production can exert a range of systemic effects on the body that can increase the risk of comorbid conditions including mood disorders, cardiometabolic disease, and osteoporosis.[15]
  • Outside of natural hormonal changes, menopause also can be induced pharmacologically and surgically following treatments for other conditions, such as ovarian cancer.[16]

Table 1: Median age, phases and features of the menopausal transition. [17], [18]

Median Age Stage Features
<47.5 years

Premenopause

(stage -3)

Regular cycles (stage -3b), followed by shortening of cycles (stage -3a). FSH levels are low.
47.5 years

Early perimenopause

(stage -2)

Frequency and length between consecutive cycles begin to change. Features variable early follicular phase FSH levels.

Late perimenopause

(stage -1)

Cycles lengthen to three to twelve months apart (stage -1), which can last between one to three years. Vasomotor symptoms are likely to begin during this stage.
51.3 years Menopause Cycles lengthen to three to twelve months apart (stage -1), which can last between one to three years. Vasomotor symptoms are likely to begin during this stage.
52.3 years

Post-menopause

(stage +1)

No menstrual cycle for >12 months (stage +1a) followed by the final phase of rapid changes in FSH levels (stage +1b), followed by established high FSH levels and low oestradiol values; lasting from three to six years (stage +1c).
>58.3 years

Late post-menopause

(stage +2)

Changes in reproductive endocrine function are established.


2. Consultation Overview

Identify Risk Factors

In Clinic Investigations- Refer to Key Drivers and the Clinical Investigation and Pathology sections below for further guidelines:

  • Determine what symptoms the patient is experiencing, including timing, frequency and severity. Provide acute management support (e.g. plant-based selective oestrogen receptor modulator [SERM] treatments) where appropriate and monitor response to treatment after six to eight weeks.
  • Explore patient’s personal and family history for risk factors[*] that may predispose patients to complications of menopausal hormonal changes (i.e. mood disorders, osteoporosis and cardiovascular disease [CVD]). In post-menopausal patients (>stage+1), investigate past and recent health screening tests, including preventative health screening (i.e. mammograms).
If patients report marked depressive and anxiety symptoms for the first time in their mid-40s or have experienced a relapse of depression during perimenopause, screen patients for mood issues using the validated Meno-D questionnaire in combination with the Metagenics Mood and Stress Questionnaire (MSQ).[19]
Screen patients using the Cardiovascular Risk Assessment Questionnaire to determine presence of CVD risk factors. Request relevant pathology testing where necessary.
Evaluate osteoporosis risk factors[†], especially in women aged over 65. Refer to the Metagenics Osteoporosis treatment protocol for further information.
  • Examine sleep hygiene and sleep patterns using the Patient Sleep Quality Tracker and the Sleep Assessment Questionnaire to assess whether inadequate sleep is a confounding factor in symptom presentation.
  • Educate patients on dietary and lifestyle practices to optimise disease prevention and support general health during the menopausal transition.
Provide patient with resources and tools to manage stress levels and manage their mental and emotional wellbeing.
Screen the patient for body mass index (BMI)[‡] and investigate physical activity to determine fitness levels.
Screen for exercise that promotes muscle strength and mass that is necessary to promote bone density (i.e. weight bearing exercise).
Discuss the benefits of maintaining regular physical movement for health and encourage patients to find activities that they enjoy. Encourage weight bearing exercise to reduce the risk of menopausal osteoporosis.

Support patients with strategies to mitigate poor nutritional habits, excessive alcohol consumption and/or smoking.

Pathology Investigations- Refer to Key Drivers and the Clinical Investigation and Pathology sections below for guidelines:

  • Diagnosis of menopause is based on history of menstrual cycles and symptoms of low oestrogen; laboratory studies are usually unnecessary.[20]
FSH and oestradiol levels are extremely variable depending on the current level of ovarian activity.[21]
For women aged 40 to 45 years with signs and symptoms of menopause or menopausal transition, basic laboratory testing to exclude non-menopausal causes of oligomenorrhea (i.e. pregnancy, hypothyroidism and hyperprolactinemia) include serum human chorionic gonadotropin (β-hCG), thyroid-stimulating hormone (TSH) and prolactin.[22]
  • Preventative health screening is recommended following menopause, including:

Cervical screening/Papanicolaou (Pap) smear, or ‘Pap test’

The National Cervical Screening Program (NCSP) in Australia and New Zealand offer different options for free cervical cancer screening.
Mammogram
BreastScreen Australia and BreastScreen Aotearoa offer free mammogram screening for perimenopausal, menopausal and post-menopausal women.
Breast self-examination may also be useful for the detection of breast changes. If detected, advise the patient to schedule a mammogram appointment or see a doctor without delay.

Further instruction can be found in Clinical Investigation and Pathology

Fasting lipids/glucose can be measured to determine metabolic dysfunction in menopausal patients that may increase the risk of CVD.

  • Screen patients for vitamin D status and plasma homocysteine as additional risk factors associated with osteoporosis and CVD.
  • To measure response to osteoporosis treatments: Biochemical markers of bone turnover (i.e. C-terminal telopeptide of type 1 collagen [CTX] for bone resorption, and procollagen type 1 N propeptide [P1NP] for bone formation)[23] may be useful for monitoring adherence to treatment and evaluation of secondary causes of bone loss.[24]

Identify Signs of Menopause [25],[26],[27]

Common symptoms of menopause include:

  • Hot flushes
  • Night sweats
  • Vaginal dryness
  • Painful intercourse
  • Insomnia and sleep disturbances
  • Mood disturbances, such as irritability and anxiety
  • Changes in sexual desire and low libido
  • Muscle and joint pain
  • Poor concentration
  • Fatigue
  • Crawling sensations on skin
  • Overall diminished wellbeing


3. Key Drivers

  • Hormonal changes within local tissues:

Oestrogen and progesterone are neuroactive steroids that influence central nervous system (CNS) function (e.g. neurogenesis and neuronal regeneration). As such, the decline of these hormones may exert changes in mood.[28]

  • Oestradiol exerts powerful effects on neurotransmitter systems (e.g. dopaminergic and serotonergic systems) that play a role in multiple aspects of behaviour including mood regulation, cognition, sleep and appetite.[29]
  • Allopregnanolone (ALLO) is a derivative of progesterone and serves as an allosteric modulator of gamma-aminobutyric acid A [GABAA] receptors, inducing anxiolytic and sedative actions.[30] As progesterone levels gradually decline during perimenopause, this naturally leads to a decrease in ALLO.[31]
These changes have been linked to heightened activity of the sympathetic nervous system, which may increase core body temperature, heart rate and blood pressure, as well as influencing endothelial function and causing insulin resistance.
These mechanisms have been linked to vascular and metabolic issues including hot flushes and metabolic dysfunction during menopause.[32]

Oestrogen is also involved in maintaining bone structure.[33]

During menopause, an osteoclast’s cellular lifespan is extended and are therefore able to resorb more bone, resulting in a high-turnover state and losses in bone mass that can lead to osteopenia.[34]

Other physiological effects of oestrogen decline include changes in the genitourinary tract leading to[35]:

Loss of dermal collagen in the vagina, bladder and urethra, resulting in thinning and loss of tissue elasticity.
Changes in vaginal flora, which occur in response to declining oestrogen levels.

In pre-menopausal women, oestrogen positively influences glycogen content in the vaginal environment, promoting lactic acid production via lactobacilli and decreasing vaginal pH.[36] Declining oestrogen levels during peri- and menopause inhibit this protective effect, subsequently increasing vaginal pH and decreasing resistance to urogenital infections.

  • Hypothalamic-pituitary-adrenal (HPA) axis dysfunction/chronic stress: HPA axis dysfunction may contribute to increased stress sensitivity, as well as depressive symptoms in midlife women.[37] Chronic stress is common during the perimenopausal period, associated with events such as caring for ageing or unwell parents, caring for children or, conversely, coping with empty nest syndrome, navigating career prospects/winding down of career and relationship shifts. Compounding these events, increased oestradiol fluctuations interact with the HPA axis, resulting in increased sensitivity to psychological stress and vulnerability to mood disturbances.[38] Further, while menopause is a naturally occurring phenomenon for most women, it can also be induced pharmacologically or surgically in certain medical situations such as hysterectomy or during cancer therapy (leading to surgical menopause), which may increase perceived stress due to the plethora of challenges that come with cancer diagnosis and therapy, as well as perceived ‘loss of youth’. Outside of this, women may also experience chronic stress due to concerns about future cancer risk or weight gain associated with menopause, as well as financial stressors, emotional hardship, and cultural perceptions and attitudes towards personal health and menopause; impacting patient ability and capacity to tolerate symptoms.[39]
  • Sleep disruption: Sleep issues are common in perimenopause, with around 50% of women reporting inadequate sleep and 26% stating it negatively impacts their quality of life and daytime functioning.[40] Sleep disruption may occur secondary to menopausal symptoms such as hot flushes,[41] which are triggered by the combination of reduced oestradiol[42] and spikes in GnRH and LH.[43] Sleep disruption may also arise secondary to onset of mood disorders during menopause, such as anxiety and depression.[44] Outside of menopause-specific drivers, sleep disruption may be due to impaired circadian rhythm associated with excess light exposure,[45] chronic or severe stress,[46] caffeine intake,[47] chronic pain,[48] thyroid disease,[49] obesity,[50] and sleep apnoea.[51]
  • Metabolic dysfunction: Obesity is associated with more frequent vasomotor symptoms compared to normal or overweight women.[52] This may be due to body fat acting as an insulator; rather than allowing heat to dissipate via normal thermoregulatory processes that maintain temperature homeostasis. This leads to increased internal body temperatures, which aggravate vasomotor symptoms.[53] In addition, the menopausal transition is associated with increased metabolic dysfunction, including increased central adiposity, greater atherogenic lipid profiles, increased low density lipoproteins (LDL) and triglycerides, and increased glucose and insulin levels.[54] These factors can increase the risk of CVD as a complication of menopause.
  • Previous mental health disorder, premenstrual syndrome (PMS) or post-natal depression (PND): Patients with a history of previous mental health disorder, PMS or PND are at greater risk of developing perimenopausal depression.[55]


4. Treatment Priorities

  • Establish baseline symptoms and screen patient for additional risk factors that may impact symptom frequency or intensity (e.g. chronic stress and inadequate sleep).
  • Determine the presence of risk factors associated with developing osteoporosis or CVD (e.g. vitamin D levels). Provide preventative support, or refer to the Osteoporosis and Cardiovascular Disease Protocol for specific treatment information.
  • Provide symptom relief to mitigate the effects of oestrogen deficiency (i.e. SERM treatments, increased dietary intake of phytoestrogens) and monitor response to treatment.
  • Determine whether patient symptoms are associated with mood disorders (e.g. anxiety and depression) using the validated Meno-D questionnaire. Provide additional symptom support to manage low mood and address HPA axis dysfunction. Refer patient for psychological support where indicated.
  • If indicated (i.e. BMI>25 kg/m2), discuss the benefits of weight loss and implement the Metagenics Shake It Practitioner Weight Management Program to achieve sustainable weight loss.
  • Evaluate whether the patient requires additional support to maintain bone health and mitigate bone loss.
  • Educate the patient on the importance of stress management, exercise and consuming a nutritionally dense diet with adequate fruit and vegetable intake, as well as quality mineral and protein food sources to support general health and wellbeing.
  • Monitor patient response to treatment, including changes in pathology where relevant (i.e. monitoring markers of CVD, bone turn over, thyroid status, vitamin D status etc.)


5. Red Flags

  • Persistent symptoms unresolved by treatments: While menopause features hallmark symptoms such as hot flushes, insomnia, mood disorders and vaginal dryness, these presentations may also indicate an underlying health condition, particularly if they do not improve following oestrogen or SERM therapy. Table 2 outlines potential differential diagnoses for common symptoms associated with other pathologies. If the patient presents with persistent symptoms, refer the patient to their General Practitioner for further investigation.
  • Comorbidity with depression or other psychiatric disorders: The perimenopause phase (between 42 to 52 years of age) carries increased risk for serious depression.[56]Approximately 45% to 68% of perimenopausal women versus 28% to 31% of premenopausal women report clinically significant elevations in depressive symptoms.[57] Research has shown greater fluctuation in oestradiol correlates with increased risk for depressive symptoms[58]; that is, the greater the variability in oestradiol concentrations the more severe the depression.[59] Lower levels of progesterone in perimenopause have been associated with an elevated risk of depression and anxiety, and higher perceived stress.[60],[61] Use the Mood and Stress Questionnaire and Depression Anxiety Stress Scale (DASS-21) questionnaire to assess the patients mental wellbeing and refer to General Practitioner/Psychologist/Psychiatrist where indicated. If patient is deemed at risk of self-harm or harm to others, seek immediate guidance from a Crisis Assessment and Treatment Team (CATT) or call Triple Zero (000) Emergency.

Table 2: Symptoms potentially present during menopause and their differential diagnoses.[62]

Symptom assessment History and examination findings (Refer to a Medical Practitioner for further investigation)
General symptoms Hot flushes

Excessive or not relieved with oestrogen or SERM therapies.

Associated with weight loss, hypertension, diarrhoea, anxiety, goitre or thyroid nodules.

Elevated serum tryptase and symptoms consistent with mast cell activation.[63]

Thyroid disease

Cancerous lesions

ast cell activation syndrome (MCAS) or systemic mastocytosis.[64]

Night sweats Lymphadenopathy Hepatosplenomegaly Weight loss Malignancy
Palpitations Associated cardiac symptoms Cardiac arrythmia
Formication (sensation of ants crawling on skin) Presence of rash New sexual partner Scabies Dermatitis Sexually transmitted infection (STI)
Myalgia and arthralgia Associated joint swelling and inflammation Rheumatoid disease (e.g. arthritis)
Migraines and headaches Accompanied by unusual focal neurological symptoms Intracranial lesion
Gynaecological/Urogenital symptoms Menorrhagia/unexplained vaginal bleeding Persistent bleeding Flooding at night Clots Anaemia or iron deficiency Fibroid Uterine polyp Endometrial hyperplasia Uterine cancer Adenomyosis Thyroid dysfunction Coagulopathies
Amenorrhoea Recent unprotected intercourse Associated factors: Galactorrhoea, headache and visual field defects. Thyroid symptoms Androgen excess Recent weight changes, eating disorders and exercise intensity. Pelvic pain or mass Pregnancy Hypothalamic dysfunction Pituitary dysfunction Ovarian tumours Thyroid disease Polycystic ovary syndrome (PCOS)
Post coital bleeding Cervical polyp Abnormal Pap smear history Cervical cancer
Family history Relevant family history of cancer: ovarian, breast, uterine or bowel cancer. Malignancy risk
Pelvic pain Palpable mass Deep dyspareunia Vaginal discharge Known history of endometriosis Ovarian or uterine cancer Endometriosis/adenomyosis Ovarian cyst Pelvic inflammatory disease
Vulval irritation Vaginal discharge Superficial dyspareunia Abnormal vulval appearance Vaginal infections: thrush and STIs Lichen sclerosis Candidiasis Vulval cancer
Sexual symptoms Loss of libido Relationship issues Associated with lethargy, tiredness and depression Bilateral oophorectomy Superficial dyspareunia Use of medications (e.g. selective serotonin reuptake inhibitors [SSRIs], oral contraceptive pill [OCP], or oestrogen) Androgen insufficiency syndrome Mood disorders Atrophic vaginitis Medication side effects Relationship breakdown
Symptoms related to new sexual partner New partner Not using condoms Partner in another sexual relationship STI
Breast symptoms Family history Relevant family history of breast or ovarian cancer Breast cancer (familial)
Breast changes Palpable lump or skin distortion Nipple discharge/eczema Abnormal screening mammogram Breast cancer Fibroadenoma Breast cyst/abscess Mammary duct ecstasia
Psychosocial symptoms Depression/Anxiety Family/past history of mood disorders, including PMS or PND. Panic attacks, phobias, sleep disturbance. Loss of motivation, loss of libido, appetite, suicidal thoughts. Current use of medications (e.g. SSRIs) Major depressive disorder Generalised anxiety disorder Specific phobias Panic disorder Bipolar disorder Schizophrenia
Memory loss Poor concentration Disorientation Cognitive disorder Dementia



6. Treatment Recommendations

Core Recommendations

Oestrogen Lifting Herbs

Dosage: For acute symptoms: Take 1 tablet three times daily. For maintenance: Take 1 tablet daily.

A combination of traditional Chinese medicine herbs including rehmannia and zizyphus for the relief of menopausal symptoms.

Mechanism of Action/Clinical Research:

  • Zizyphus is used for the treatment of heightened sympathetic nervous activity leading to anxiety, insomnia, sweating, night sweats and palpitations.[65]
  • Twenty-two menopausal women (average age 50.6 years) were randomly allocated to receive either the herbal formula, containing rehmannia, Asiatic cornelia cherry, Chinese yam, zizyphus, tree peony, poria, water plantain and anemarrhena, or placebo for two months. The herbal formula was associated with significant improvements in menopausal symptoms, including flushing, lower back pain and anxiety. Supplementation with the herbs also significantly increased serum oestradiol levels.[66]

 

To support mood symptoms:

 

Meta Mag Magnesium, Taurine and Glutamine for Stress

Dosage: Add 2 level scoops (11.9 g) to 200 mL of water, twice daily.

A combination of Meta Mag® magnesium, taurine, zinc and vitamin B6 to decrease excessive neuronal activity in the amygdala and reduce catecholamine levels, to support a healthy stress response and reduce the effects of physical and psychological stress on the body.

Mechanism of Action/Clinical Research:

  • Magnesium improves resistance to neuropsychological stressors, such as glutamate excitotoxicity, through its actions as a voltage-gated antagonist at the glutamate, N-methyl-D-aspartate (NMDA) receptor site.[67] The reduction of glutamate activity has been shown to increase the actions of the GABAergic systems.[68]
  • Taurine acts as an inhibitory neurotransmitter or neuromodulator, interacting with NMDA receptors to suppress glutamatergic transmission and protect against glutamate excitotoxicity.[69]
  • Zinc acts as an inhibitory neuromodulator of glutamate release, regulating NMDA receptors.[70]

A study of 100 adolescent female students with mood disorders found decreased serum zinc to be inversely correlated with symptoms of anxiety and depression.[71]

  • L-Glutamine is involved in neurotransmitter synthesis and is the precursor for glutamate and GABA.[72]
  • Vitamin C (ascorbic acid) is required for the synthesis of neurotransmitters, including noradrenaline and serotonin.[73]
  • Vitamin B6 is fundamental to the production of many neurotransmitters[74] and is specifically involved in the creation of histidine to histamine, tryptophan to serotonin, glutamate to GABA, and dihydroxyphenylalanine to dopamine,[75] as well as the synthesis of adrenaline and noradrenaline.[76]

 

PLUS

Vitamins B5, B6 and C for Stress and Adrenal Health

Dosage: Take 1 tablet twice daily with food

A high-dose blend of active B vitamins and vitamin C that support neurotransmission and steroid hormone synthesis, to regulate HPA axis activity (adrenalin, noradrenaline and cortisol synthesis) and sympathetic and parasympathetic arms of the stress response.

Mechanism of Action/Clinical Research:

  • Vitamin B5 forms part of coenzyme A (CoA), which is essential for the production of acetylcholine[77] CoA is also required for the synthesis of steroid hormones including cortisone.[78]

A meta-analysis investigating the effects of multivitamin supplementation on mood and mild psychiatric symptoms demonstrated significant improvements in perceived stress levels, mild psychiatric symptoms and anxiety, with the most pronounced effects attributed to high-dose B vitamin use.[79]

  • Vitamin B6, is a vital cofactor for transaminase enzymes, which are fundamental in the creation of GABA, dopamine, histamine and serotonin.[80] Research also suggests that vitamin B6 diminishes sympathetic output and acts peripherally to blunt the physiological impact of corticosteroids.[81]
  • Biotin (vitamin B7) is an important cofactor for the enzyme pyruvate carboxylase, which is involved in cortisol production.[82]
  • Vitamin C has involvement in dopamine production and is required for the activity of enzyme, dopamine β-hydroxylase (dβh), which requires vitamin C as a cofactor.[83]

 

PLUS

Lpc-37 and 299v for Gut-Brain Axis Support, Emotional Wellbeing and Stress Response

Dosage:

To support mental wellbeing and mood: Take 1 capsule daily.

To support neuroendocrine function and a healthy stress response: Take 2 capsules daily.

An evidence-based combination of Lactobacillus paracasei Lpc-37 and Lactobacillus plantarum 299v to mitigate stress-induced cortisol elevation and support a healthy mood by enhancing vagal nerve activity. 

Mechanism of Action/Clinical Research: 

  • Supplementation with Lpc-37 in animals and humans normalised cortisol levels in low grade chronic stress and prevented stress-induced anxiety and depressive-like behaviour.[84]
  • In a randomised, double-blind, placebo-controlled trial, 1.75 billion colony forming units (CFU)/d of Lpc-37 has been shown to support the gut-brain axis and improve resilience to stress.[85] Taken over five weeks by 113 patients, Lpc-37 was shown to improve patient heart rate in response to stress, reduce perceived stress and normalise night cortisol levels.[86]
  • In a randomised double-blind, placebo-controlled study, 10 billion CFU/d of 299v administered over 14 days significantly reduced cortisol levels compared to placebo (p<0.05).[87]
  • 20 billion CFU/d of 299v over eight weeks has been shown to improve cognitive function in patients with major depressive disorder.[88]

 

PLUS

Symptomatic mood support:

If with low mood:

Mood, Adrenal and Thyroid Support

Dosage: Take 1 capsule twice daily with food

A combination of anti-fatigue and mood enhancing botanical extracts and nutrients, including St John’s Wort, withania, rhodiola, S-adenosyl methionine (SAMe) and iodine to mitigate HPA dysfunction to assist in the management of low moods.

Mechanism of Action/Clinical Research:

  • St John’s wort has been shown to modulate the activity of mood-enhancing neurotransmitters including serotonin dopamine, noradrenaline and GABA.[89]

Findings of a 2016 meta-analysis supports the efficacy of St John’s Wort for the management of mild to moderate depression, with outcomes observed at doses between 600 mg/d to 1,800 mg/d to be equally beneficial as SSRIs.[90]

  • Rhodiola contains phenolic compounds (phenylethane derivatives) that are structurally related to adrenaline and dopamine, involved in mood regulation.[91] Rhodiola has also been found to mitigate reduced brain neuroplasticity, associated with maladaptive stress responses.[92]

Rhodiola has also been demonstrated to be effective in the treatment of mild to moderate depression in 91 individuals receiving either 340 mg/d or 680 mg/d for six weeks compared to placebo.[93]

  • Withania has been found to up-regulate stress-protective neuropeptide, urocortin, while downregulating corticotropin-releasing hormone (CRH) activity, therefore modulating HPA activity.

In a randomised, double-blind, placebo-controlled study conducted over eight weeks, 52 patients experiencing chronic stress received either 600 mg/d of withania or placebo. Positive results of the study demonstrated significant reductions in perceived stress after four and eight weeks of supplementation (p<0.02) and lower cortisol levels compared to baseline (p<0.033).[94]

  • SAMe serves as a methyl donor within methylation,[95] supporting neurotransmitter activity and nerve membrane receptor functions required for healthy neuronal communication.[96]

In a 2010 study, researchers found that 1,600 mg/d of SAMe led to higher rates of remission from major depressive symptoms in participants who failed to respond to SSRIs.[97]

  • Adequate iodine status is required to produce thyroid hormones, which is important in maintaining a healthy mood and energy metabolism.[98]

 

OR

BCM-95 Turmeric and Saffron for Depression

Dosage: Take 1 capsule twice daily with food

An anti-inflammatory blend of BCM-95 Turmeric and saffron to reduce excess HPA axis activation, preventing stress-induced elevation of cortisol and glutamate excitotoxicity, while also increasing brain-derived neurotrophic factor (BDNF) production for enhanced neurogenesis.

Mechanism of Action/Clinical Research:

  • Safranal and crocin, present in saffron, have been shown to reduce HPA axis activity and decrease stress-induced plasma corticosterone levels.[99]
  • Safranal has also been shown to have anxiolytic and sedative effects via innervation of the GABAergic pathway.[100]

In a 2021 randomised, placebo-controlled study, 82 perimenopausal women (mean age 49.2 years) received either 28 mg saffron extract (affron®) daily or placebo.[101] After 12 weeks, there was a 33% reduction in anxiety and a 32% reduction in depression scores.

  • Turmeric activates glutamate decarboxylase, which converts glutamate to GABA.[102]
  • Turmeric exerts anti-inflammatory effects and has been shown to modulate dopamine, serotonin and noradrenaline in the brain.[103]

A randomised, double-blind, placebo-controlled study involving 123 participants that were prescribed 500 mg/d of BCM-95 Turmeric combined with 30 mg/d of saffron revealed significant reductions in anxiety and depressive symptoms after 12 weeks.[104]

  • Doses of 250 mg BD to 500 mg BD of curcumin have proven effective for ameliorating depressive symptoms.[105]

  

If Experiencing High Levels of Irritability

Bupleurum Complex for Nervous Tension and Irritability

Dosage: Take 3 capsules twice daily with food.

A traditional combination of Chinese botanical extracts, including bupleurum, Chinese peony, dong quai and liquorice to relieve the symptoms of stress and nervous tension, including emotional irritability.

Mechanism of Action/Clinical Research:

  • Bupleurum, Chinese peony and liquorice has been shown to exert both anxiolytic and antidepressant-like effects through several mechanisms, such as regulating tryptophan metabolism.[106]

A systematic review of nine publications confirmed that the traditional bupleurum combination containing bupleurum, Chinese peony, atractylodes, nutgrass, dong quai, poria, tree peony, gardenia, peppermint and ginger was more effective than hormone replacement therapy (HRT) in diminishing menopausal symptoms (including depression, hot flushes, fatigue and insomnia), with fewer side effects.[107]

In a systematic review of 26 studies involving 1,837 patients with depression concluded that the combination of herbs was effective in improving depressive symptoms, comparable to antidepressants but with less adverse effects.[108]

 

OR

Vitex, Ginger and Withania to Increase Progesterone

Dosage: Adults: Take 1 tablet once daily with food.

A blend of vitex, ginger, zinc and vitamin B6, in combination with HPA axis-regulating and mood-supporting withania, to help balance mood via enhancing progesterone production and activity.

Mechanism of Action/Clinical Research:

  • Vitex modulates stress-induced prolactin secretion and increases progesterone biosynthesis by up-regulating dopaminergic action.[109],[110],[111]

An eight-week randomised controlled trial confirmed the efficacy of Vitex agnus-castus (chaste tree) in a group of 52 women (mean age 52.5 years). Vitex was shown to reduce menopausal symptoms including depression and anxiety.[112]

  • Vitamin B6, is a vital cofactor for transaminase enzymes, which are fundamental in the creation of GABA, dopamine, histamine and serotonin.[113] Research also suggests that vitamin B6 diminishes sympathetic output and acts peripherally to blunt the physiological impact of corticosteroids.[114]
  • Zinc acts as an inhibitory neuromodulator of glutamate release, regulating NMDA receptors.[115]

A study of 100 adolescent female students with mood disorders found decreased serum zinc to be inversely correlated with symptoms of anxiety and depression.[116]

  • Withania modulates serum cortisol levels, improving resilience towards stress and reducing its contribution to mood symptoms.[117],[118]

In a randomised, double-blind, placebo-controlled study conducted over eight weeks, 52 patients experiencing chronic stress received either 600 mg/d of withania or placebo. Positive results of the study demonstrated significant reductions in perceived stress after four and eight weeks of supplementation (p<0.02), as well as lower cortisol levels compared to baseline (p<0.033).[119]

 

If anxious and tense:

Herbal Support for Hyper HPA and Stress

Dosage: Take 1 tablet three times daily

A combination of anxiolytic herbs including ziziphus, passionflower, kudzu and magnolia that enhance GABA activity, working against glutamate-mediated excitability in the brain to alleviate anxiety, nervous tension and agitation.

Mechanism of Action/Clinical Research:

  • Zizyphus has been shown to modify the GABAA receptor subunits expressional levels,[120] which opposes glutamate-mediated excitability in the brain, contributing to its anxiolytic effects.[121]
  • Passionflower has been found to modulate the GABA system, demonstrating an affinity for both GABAα and GABAB receptors, increasing its inhibitory effects.[122]

A clinical trial involving 154 participants with prolonged nervous tension were treated with 1,020 mg/d of passionflower for 12 weeks. Passionflower significantly improved stress-associated symptoms including restlessness, sleep disturbances, exhaustion, anxiety, poor concentration, nausea, tremors, and palpitations.[123]

  • Kudzu has demonstrated β-adrenoceptor blocking activity[124],[125] similar to pharmacological beta-blockers, which are used to reduce the physical effects of anxiety and stress such as palpitations, high blood pressure, tremor and sweating.
  • Magnolia exhibits muscle relaxing effects via GABAergic mechanisms,[126] as well as neuroprotective properties.[127],[128]

 

If wired and tired:

Rehmannia Complex for Nervous Exhaustion

Dosage: Take 2 tablets twice daily with food.

An effective combination of anxiolytic and adaptogenic herbs including American ginseng, rehmannia, wild oats and lavender to support healthy CNS and HPA axis function during times of prolonged stress.

Mechanism of Action:

  • Ginsenosides, contained within American ginseng, interact with GABAA receptors to provide inhibitory and anxiolytic actions. Ginsenoside Rg3, the most active ginsenoside, also regulates voltage and ligand-gated ion channel activity, modulating nerve activity and supporting brain channel regulation.[129]
  • Wild oats extract has been found to inhibit the enzymes, monoamine oxidase-B (MAO-B) and phosphodiesterase 4 (PDE 4),[130] which degrade monoamine neurotransmitters. This action increases the availability of monoamine neurotransmitters at the synapse.
  • Constituents in lavender, specifically linalool and linalyl acetate, are proposed to act on GABAA binding receptors in the CNS inducing a relaxed state.[131]

 

If experiencing insomnia and sleep issues

Magnesium with Lutein and Zeaxanthin for Sleep Pattern Support

Dosage: Add 1 scoop (5.7 g) in 200 mL of water once daily in the evening.

Meta Mag magnesium bisglycinate, ornithine, ashwagandha, lutein and zeaxanthin to address disrupted sleep cycle patterns, potentiate slow-wave sleep (SWS), enhance melatonin levels and reduce elevated cortisol. These ingredients may improve sleep quality and help to mitigate fatigue.

Mechanism of Action/Clinical Research:

Magnesium supplementation has been shown to improve sleep quality, and when used in combination with withania and ornithine, regulates circadian rhythm by modulating serotonin turnover and the HPA axis response to stress.[132],[133],[134],[135]

Magnesium has been shown to significantly decrease serum cortisol levels within hours of sleep initiation, resulting in increased in SWS (p<0.01).[136]

500 mg/d of elemental magnesium over eight weeks was shown to significantly increase sleep time and sleep efficiency, while improving sleep onset latency (p<0.03).[137] Patient serum cortisol levels were shown to decrease (p<0.008) in correspondence with increased in melatonin (p<0.007), indicative magnesium’s effect on improving sleep quality.[138]

Ornithine improves sleep quality, as well as reducing stress markers through the regulation of cortisol and dehydroepiandrosterone sulfate (DHEAS) production.[139]

In a double-blind, randomised, placebo-controlled trial, 52 participants who received 400 mg of L-ornithine for eight weeks reported improved sleep quality, including enhanced sleep initiation and maintenance.[140] L-ornithine was shown to reduce serum cortisol and improve cortisol/dehydroepiandrosterone sulfate (DHEAS) ratio indicative of its beneficial effects on HPA axis function.[141]

Withania been shown to moderate cortisol levels, which may counteract stress-induced HPA axis overactivity in insomnia.

In a study conducted in 60 healthy individuals receiving either 250 mg/d and 600 mg/d of withania over eight weeks, participants showed significant improvement in perceived stress scores, reductions in morning cortisol and enhanced sleep quality in both treatment groups (p<0.05).[142]

Lutein and zeaxanthin support the production and release of melatonin.[143],[144]

Supplementation of 20 mg/d of lutein and 4 mg/d of zeaxanthin in 48 healthy adults was shown to improve the incidence of sleep disturbances over six months, reduce the need for sleep-enhancing medications, and improve Pittsburgh Sleep Quality Index scores(p<0.05).[145]

 

OR

California Poppy and Passion Flower for Sleep 

Dosage: For insomnia, take 2 tablets once daily with your evening meal.

Passionflower, zizyphus, lavender oil and California poppy to modulate neurotransmitter pathways, including GABA and glutamate, monoamine and catecholamine activity (which support sleep quality), HPA function, formation of synaptic pathways, and brain plasticity.

Mechanism of Action:

  • Zizyphus activates glutamic acid decarboxylase, which catalyses GABA synthesis, while also sensitising GABA receptors by increasing their subunit expression.[146]
  • Lavender oil promotes a GABAergic response by blocking calcium ion channel activity within neurons and suppressing glutamate excitation, with inhibitory effects comparable to those seen in pregabalin (a pharmaceutical agent that mimics the effects of GABA).[147]
A double-blind, randomised, multi-centre trial involving 170 patients that were prescribed 80 mg/d of lavender oil for 12 weeks showed significant improvements in in anxiety and sleep quality.[148]
California poppy stimulates binding of the GABAAreceptor site, providing sedative effects.[149]

 

To support bone health:

Hydroxyapatite and Soy for Osteoporosis

Dosage: Take 2 tablets twice daily with food OR Add 1 scoop (3.9 g) to 200 mL of water twice daily with food. Stir well and take immediately.

A clinically effective combination of soy isoflavones, hydroxyapatite calcium, vitamin D and trace minerals to improve bone formation and density and slow the progression of osteoporosis.

Mechanism of Action/Clinical Research:

Microcrystalline hydroxyapatite (MCHA) contains all the natural elements of healthy bone in a protein-mineral complex, providing calcium and phosphorus in the ideal 2:1 physiological ratio for bone mineralisation.[150]

In women with osteoporosis, MCHA providing 712 mg/d elemental calcium vs. 1000 mg/d of elemental calcium from calcium carbonate in addition to a vitamin D (266 µg/d) lowered the rate of bone mineral density (BMD) loss over three years more significantly in the MCHA group (p<0.05).[151]

Glycine max (Soy Isoflav-One™) extract is a non-genetically modified soybean extract containing a minimum of 40% isoflavones that act as SERMs through their phytoestrogenic actions.

Isoflavones have been shown to inhibit osteoclast proliferation and decrease bone resorption by osteoclasts.[152]

A meta-analysis including data from 1,240 menopausal women demonstrated ingestion of 82 mg/d of soy isoflavones for 6 to 12 months significantly increased spine BMD by an average of 2.38% (p<0.001) compared to controls.[153]

800 IU/d of vitamin D in combination with calcium may decrease the incidence of non-vertebral fractures by 10% to 20%, especially in persons in the older age groups with lower baseline vitamin D.[154]

Boron plays a role in calcium balance through a number of different mechanisms, in particular, helping to reduce urinary calcium excretion and enhance calcium absorption.[155]

Zinc may modulate the anabolic effect of insulin-like growth factor I (IGF-1) in osteoblasts, and may enhance the proliferative effect of oestrogen on these cells.[156]

 

If vitamin D levels are <50 nmol/L:

Vitamin D3

Dosage: Take 1 capsule daily with food.

A concentrated source of vitamin D to prevent the progressive decline of BMD in osteoporosis. Vitamin D deficiency (<30 to 50 nmol/L) is one of the most common causes of impaired skeletal mineralisation.[157]

Mechanism of Action/Clinical Research:

In patients at risk of vitamin D deficiency, the Endocrine Practice Guidelines committee suggest that the daily requirement for adults is between 1,500 IU to 2,000 IU/d, with a tolerable upper intake level of 10,000 IU per day.[158]

Individuals with a frank deficiency will require higher doses of vitamin D, generally around 4,000 IU/d for eight to twelve weeks to correct deficiency.[159]

In a randomised double-blind placebo-controlled study, 1,000 mg/d of calcium carbonate in addition to 800 IU/d of vitamin D over 12 months in vitamin D deficient women aged >65 years (17 nmol/L) resulted in substantial increases in BMD.[160]

In a systematic review, vitamin D between 700 IU/d to 800 IU/d was shown to reduce the risk of hip and nonvertebral fractures in ambulatory or institutionalised elderly persons compared to 400 IU/d.[161]



7. Supportive Programs

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8. Diet and Lifestyle Recommendations

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9. Clinical Investigation and Pathology

Clinical Screening Rationale

 

Pathology Testing  Ideal Reference Range Rationale


10. Pharmaceutical Treatments

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Product SSRIs/SNRIs Benzodiazepines HRT


11. Additional Resources

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12. Footnotes

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13. References

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