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The transition into menopause is a normal biological process in a woman’s life. Specific traditional medicines and nutritional treatment interventions may be effective to naturally assist with the management of peri-menopausal symptoms.

Perimenopause
Perimenopause, also known as the climacteric or menopausal transition is defined as the hormonal period around and leading up to menopause.[1],[2] Perimenopausal symptoms occur approximately 10 years to 12 months prior to menopause, usually remaining for three to five years.[1],[2]

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Background
Ovarian follicle production gradually slows during perimenopause, marked by a decrease in levels of inhibin and anti müllerian hormone (AMH), fluctuating levels of follicle stimulating hormone (FSH), estrogen, luteinizing hormone and menstrual cycle irregularity.[1],[3],[4] Progesterone levels also lower with reduced ovulation. The hypothalamo-pituitary-ovarian axis governs changes to reproductive hormones and peptides during this life stage. These changes can result in irregular patterns of estradiol and progesterone, particularly in the later stages of menopausal transition.[4] Reduced central nervous system sensitivity to estrogen’s negative and positive feedback outcomes is also evident.[4] Changes may vary from person to person and from month to month, with menses becoming lighter, heavier and more-or-less frequent.[1],[5],[6] Generally, estradiol levels remain relatively stable during early perimenopause with some women experiencing elevated levels.[5]

There is no specific test for verifying perimenopause.[5] The Stages of Reproductive Ageing Workshop (STRAW) criteria, consider blood tests unnecessary to determine this life stage, however testing FSH may be useful in some cases along with luteal phase progesterone to check ovulation.[5],[7] Thorough case taking including menstrual cycle history and client symptomology are generally considered when identifying menopausal transition. It is also a time when further health assessments may be undertaken.[3],[5]

Women may also experience symptoms such as sleep disturbance, changes in libido, hot flushes, headaches, breast tenderness, anxiety, depression, irritability and weight gain. Vaginal dryness may also occur closer to menopause.[3],[5]

Lifestyle factors associated with symptom reduction include; the consumption of a healthy diet, adequate sleep and physical activity, stress reduction, avoidance or lowered caffeine and alcohol intake, reduced intake of spicy food and hot drinks and the use of water based lubricants where appropriate.[1],[2],[8]

The Menstrual Cycle and Estrogen Metabolism
The menstrual cycle is an essential life rhythm, governed by interacting levels of progesterone, estrogens, follicle stimulating hormone (FSH), and luteinizing hormone (LH).[9] Estrogens are a group of three biochemically distinct hormones, estradiol (E2), estrone (E1), and estriol (E3). Estrogens are metabolized down three distinct pathways leading to the formation of a range of active metabolites.

Metabolism of estrone (E1) and estradiol (E2) by cytochrome P450 enzymes leads to the generation of hydroxy estrogen metabolites which include 2-hydroxy estrone (2OHE), 4-hydroxyestrone (4OHE), and 16alpha-hydroxyestrone (16OHE).

The 2OHE and 4OHE metabolites are rapidly converted to the methoxy estrogens by catechol-O-methyltransferases (COMT). E1 and E2 metabolites are maintained in equilibrium through the actions of 17β-hydroxysteroid dehydrogenase 1 and 2 enzymes.[10]

The 2-OH pathway is considered safer as the 2OHE metabolites demonstrate reduced hormonal potency. This attribute may hold benefit in cases of elevated estrogen during the early stages of perimenopause.[3],[11] Conversely, the 4-OH pathway is considered highly genotoxic as these metabolites can create reactive compounds that damage DNA. The third pathway creates 16OHE which is the most estrogenic of the metabolites, although this metabolite is still considerably less estrogenic than estradiol.

Knowing the 2, 4, and 16 estrogen metabolite ratio is clinically important as a variety of treatment interventions can be helpful in restoring and maintaining a healthy balance.

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CAMS to Relieve Symptoms Associated with Perimenopause
A variety of nutritional interventions may be useful during perimenopause on a case by case basis to support general health and wellbeing. A number of these are listed below.

Bioavailable Diindolylmethane (DIM) to Support Healthy Estrogen Metabolism
Cruciferous vegetables such as cabbage, Brussels sprouts, cauliflower, and broccoli contain a precursor phytochemical known as glucosinolate which is further broken down by the plant enzyme myrosinase to yield a bioactive compound known as Indole 3-carbinol (I3C).

I3C is rapidly converted to numerous compounds including one predominant bioactive compound known as 3,3′-diindolylmethane (DIM).[12] Microencapsulated DIM is now the most studied I3C-derived compound and is regarded as the supplement of choice to modulate healthy estrogen metabolism.[13],[14],[15],[16],[17]

Research shows supplemental DIM specifically assists activity of hepatic cytochrome P450 enzymes, CYP1A2 and to a lesser extent CYP1A1, necessary to promote greater 2-hydroxylation of estrogens.[1],[5],[18] This effect is possible using DIM at physiologically achievable doses.[3]

In a study published in the Journal of the American Nutraceutical Association microencapsulated DIM was shown to improve symptoms of cyclical mastalgia in premenopausal women[19],[20] Breast pain and tenderness that occurs during the luteal phase is a marker of breast susceptibility to estrogen. It is also a symptom associated with menopausal transition.[1],[2] The researchers found there was a significant reduction in the severity and duration of recurrent breast pain when compared to healthy controls.

Iodine and Selenium Assist Thyroid Hormone Production
Perimenopausal symptoms may be similar to those of thyroid dysfunction and may occur concurrently in some women[21] Thyroid function tests can be performed if disease is suspected.

Nutrients that support thyroid function include iodine and selenium[22] Bladderwrack (Fucus vesiculosus) is a traditional thyroid tonic that is a natural source of iodine, and other trace elements including fucodins.[23],[24]

Iodine is a micronutrient that supports various physiological functions and is therefore of crucial importance for the health and well-being of all individuals.[25],[26]

A healthy adult body contains 15-20 mg of iodine, 70-80% of which is stored in the thyroid.[27] Women have an increased demand for iodine which is likely due to the increased uptake by breast tissue, in addition to the thyroid gland, where iodine plays an important role in supporting breast health.[28]

In adults, the thyroid is the organ with the highest amount of selenium per gram of tissue as this essential micronutrient is required for antioxidant function, and metabolism of thyroid hormones.[29] Selenium soil content varies in Australia, consequentially effecting plant concentrations.[30]

Research shows thyroid hormones influence a variety of molecular mechanisms including the regulation of the menstrual cycle. Effects are due to both the direct action of thyroid hormones in the reproductive organs, and the action of these hormones on the bioavailability of other hormones and growth factors that are also necessary for the proper functioning of the female reproductive system.[31] Typically, thyroid dysfunction causes a short luteal phase, and inadequate progesterone production.[32]

Both estrogen and thyroid hormones play a role in modulating brain GABA-ergic, serotonergic and noradrenergic systems.[33],[34]

Cholecalciferol (Vitamin D3) Assists Maintenance of Bone Integrity
Vitamin D deficiency is prevalent with a global trend observed in all age groups.[35],[36] In Australia, nearly one third of adults have less than optimal vitamin D levels despite the fact we live in a relatively sunny climate.[37],[38]

The prevalence of vitamin D deficiency may be due to insufficient sun exposure, lowered intestinal absorption associated with compromised gut function, reduced ability to activate vitamin D from the diet, or polymorphisms in the vitamin D receptor (VDR) gene.[39]

Vitamin D is an important nutrient for bone health and enhances calcium metabolism. The later stages of menopausal transition are associated with increased rates of bone loss. This includes the two years leading up to menopause, particularly the year preceding menopause and the following two years after last menstruation.[40]

Often termed the ‘sunshine vitamin’, receptors for vitamin D are found throughout the body, including genes and many types of cell membranes.[41] Therefore, this nutrient has many biological functions beyond bone health.[42]

Vitamin D3 plays a vital role in stimulating a healthy immune response. Lower vitamin D status is observed in individuals with hypothyroidism, and autoimmune thyroid diseases (AITD) such as Hashimoto’s thyroiditis (HT) and Graves’ disease (GD).[43],[44]

Supplementation with vitamin D is appropriate to address a deficiency, and is particularly important in obese, and insulin resistant women.[45] Over time supplementation can have a positive effect on raising serum 25-hydroxyvitamin D [25(OH)D] concentrations.[46]

Supporting Mental and Emotional Wellbeing
Supporting a healthy stress response in the body is profoundly important during menopausal transition. Stress, along with declining levels of estrogen can exacerbate perimenopausal symptoms. An increase in brain and baseline plasma norepinephrine and high overall cortisol has been associated with hot flush severity in some individuals.[47],[46] GABA agents have been demonstrated to reduce hot flushes in some cases.[48] There are inconsistent results regarding the use of serotonergic substances to reduce hot flushes.[46]

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Relief of Symptoms of Stress
Nutrients that reduce the symptoms of stress include B vitamins, magnesium (Mg).[49],[50],[51]

A recent systematic review and meta-analysis confirmed that there is evidence to suggest a positive effect for B vitamin supplementation for mood outcomes in both healthy and at-risk populations. Examining each of the set mood parameters in detail, the research confirmed B vitamin supplementation significantly reduced the symptoms of stress.[46]

Marked stress is associated with increased Mg excretion via the urine.[48],[52],[53] Mg helps regulate hypothalamic pituitary adrenal axis (HPAA) activity and the body's stress response. Supplementation has been demonstrated to lessen HPAA activity.[54],[55] A systematic review investigating Mg supplementation for subjective anxiety and stress, showed supplementation reduced subjective anxiety in predisposed participants. Unfortunately, no studies in the review included validated measures for stress outcomes, therefore further randomized trials are warranted.[47]

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter, widely distributed throughout the central nervous system (CNS).[56] PharmaGABA® is a supplemental form of GABA produced from lactobacillus hilgardii that may support a healthy stress response and relieve sleeplessness.[57],[58] PharmaGABA® may help relieve nervous tension, stress and mild anxiety. A study investigated the effects of orally administrated PharmaGABA® on alpha and beta waves of the CNS in healthy subjects as well as measuring salivary IgA levels during times of stress.[54] Alpha waves are generated when an individual is relaxed, yet alert. In contrast, low amplitude beta waves increase in stressful situations and make mental concentration difficult. In general, a greater alpha to-beta ratio is associated with a more relaxed and alert state. Based on the results 100mg of PharmaGABA® led to a significant increase in alpha waves and a decrease in beta waves compared to the control group.[54] Chronic insomnia is common and often associated with long term health problems such as obesity, hypertension and mood swings.[59],[60] Insomnia peaks from 45-64 years of age and a second increase appears in people 85 and older.[61] Further, insomnia is especially common during peri-menopause and is strongly associated with the use of sleeping medications which can have adverse effects.[62]

Due to its effects on relaxation PharmaGABA® may be considered a natural sleep aid to support the relief of insomnia. PharmaGABA® is non-addictive and does not result in daytime drowsiness. The results of a small randomized, single-blind, placebo-controlled crossover trial were recently published in the Journal of Food Science and Biotechnology.[55] The researchers demonstrated the effectiveness of oral PharmaGABA® administration for shortened sleep latency and deep non-REM sleep. Participants classified as poor sleepers via the Pittsburgh Sleep Quality Index Questionnaire (PSQI) were given PharmaGABA® at a dose of 100mg in powder form or a placebo 30 minutes before they went to bed. Results were measured via EEG recordings, Visual Analogue Scale Questionnaires (VAS) and PSQI. GABA administration resulted in a 5-minute reduction in sleep latency (a 50% reduction). GABA also significantly increased total non-rapid eye movement (non-REM) sleep by 2.2%.[55]

An additional study showed GABA supplementation moderated the stress markers salivary cortisol and chromogranin A in participants that undertook an arithmetic task.[63]

Addressing lifestyle factors that include maintaining healthy dietary habits, adequate physical activity, moderation of alcohol and caffeine intake, stress-management techniques and supplementation where appropriate may ameliorate transition through to menopause.

Advisory Statements
Health professionals should be aware that some studies indicate Vitex agnus-castus may bind oestrogen and dopamine receptors which suggests the potential for interaction with medications that have estrogenic and/or dopaminergic actions.[64] Combined use with certain medicines, including oral contraceptives and other medicines with hormonal and/or dopaminergic actions, may result in decreased efficacy or additive effects, although there is limited evidence to verify the extent of these effects.
Harmless changes in urine color may occur with taking microencapsulated DIM. Increased water consumption can reduce this side effect.
Symptoms of nausea and/or headaches may occur with microencapsulated DIM. Microencapsulated DIM assists activity of hepatic cytochrome P450 enzymes (CYP1A2) pathways. Nutrients required to support phase 2 liver detoxification pathways can assist in reducing these symptoms.
A short-term increase in symptoms with microencapsulated DIM may be due to increased metabolism of available estrogen.
Microencapsulated DIM does not contain goitrogenic compounds which could affect thyroid function.
Microencapsulated DIM is not phytoestrogenic and has no inherent estrogenic activity. It may be used in used in conjunction with phytoestrogenic herbs.
Microencapsulated DIM may assist hormone health when taken with Hormone Replacement Therapy (HRT). Microencapsulated DIM may assist effective metabolism of increased available estrogen when taken with bioidentical hormone replacement therapy (BHRT).
Microencapsulated DIM may assist hormone health when taken with the oral contraceptive pill (OCP). Microencapsulated DIM has no inducing action on CYP3A4, the enzyme that metabolizes the OCP. Therefore, microencapsulated DIM does not affect efficacy of the OCP.
Combined use of microencapsulated DIM and Tamoxifen is not recommended.
Combined use of microencapsulated DIM and Zoladex is supported.
Microencapsulated DIM should be used with caution in patients taking anticoagulation medications.
Individuals on prescribed medications that are metabolized down the CYP1A1/1A2 pathways should seek medical advice. Example; microencapsulated DIM may lead to a moderate increase in the drug Olanzapine.
Microencapsulated DIM is not recommended for use if you are pregnant, breastfeeding, or planning a pregnancy. The safety of microencapsulated DIM during pregnancy and breastfeeding has not been established.

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