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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 50-57

Talking about hot flashes (潮热)

Master of Traditional Chinese Medicine, Course Organizer at the Shanghai Qigong Research Institute, Shanghai 200030, China

Date of Submission04-Dec-2020
Date of Acceptance05-Feb-2021
Date of Web Publication31-Mar-2021

Correspondence Address:
Dr. Anna Bogachko Holmblad
Shanghai Qigong Research Institute, Shanghai 200030
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CMAC.CMAC_6_21

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Women worldwide are dealing with hot flashes (潮热), a perimenopausal feature that is often tiring, embarrassing, and energetically draining. Conventionally, Chinese medicine defines hot flashes as Kidney-yin deficiency and its clinical manifestations include red face, sweating, hot sensations in the palms and soles, mouth and nose dryness, constipation, insomnia, lumbar soreness, knee weakness, red tongue, etc. To obtain a broader perspective and understand the dynamics of hot flashes, we examined the mechanisms behind hot flashes based on both the knowledge from ancient Chinese medicinal texts, as well as novel research findings of Chinese and Western medicine. This perspective was the foundation for the acupuncture study of our traditional Chinese medicine conducted in 2018–2019 in Shanghai. This study, designed as a pragmatic randomized control trial with two parallel groups, focused on regulating and unblocking conception and governor vessels. The results confirmed that our acupuncture method could effectively reduce both the frequency and severity of hot flashes and improve life quality of middle-aged women.

Keywords: Hot flashes (潮热), kidney, menopause, perimenopause, syndrome differentiation (辩证), traditional Chinese medicine (TCM), trial

How to cite this article:
Holmblad AB. Talking about hot flashes (潮热). Chin Med Cult 2021;4:50-7

How to cite this URL:
Holmblad AB. Talking about hot flashes (潮热). Chin Med Cult [serial online] 2021 [cited 2021 Jul 27];4:50-7. Available from: https://www.cmaconweb.org/text.asp?2021/4/1/50/312779

Abbreviations: TCM– Traditional Chinese Medicine, HRT– Hormone Replacement Therapy, HPO– Hypothalamic Pituitary Ovarian (axis), HPA– Hypothalamic Pituitary Adrenal (axis), CV– conception vessel, GV– governor vessel, SP– Spleen meridian, KI– Kidney meridian, HT– Heart meridian.

  Introduction Top

A group of smartly dressed, jolly women takes their seats with a cup of herbal tea handy in front of them [Figure 1]. Curious about the traditional Chinese medicines (TCMs) perspective on their menopausal concerns and especially the troublesome hot flashes, they are all attentive. The first PPT slide for our course is a picture showing the typical symptoms during the menopausal transition: fatigue, irritation, mood swings, hot flashes, hyposexuality, anxiety, and irregular sleeping patterns. Instantly, they all burst out in unison: “Oh, I have all of them!!.”.
Figure 1: Drinking Chinese herbal tea at our workshop on hot flashe

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When sneaking through the door of perimenopause at the age of 45–55, women embark on a journey taking them into unknown territory of bodily experiences accompanied by new thoughts and emotions. The shift from being in phase with a monthly cyclic flow to the stage when periods eventually stop is the transformation period when women tend to feel more tired, worried, and anxious. Many women face the nuisance of hot flashes, sleepless nights, soaked bed linens, discomfort, and extreme fatigue, thus amplifying their symptoms. Even if we are all told this will happen, women are a bit taken aback by perimenopause, leading up to menopause and the end of their fertile years. This transition is a time for reflection and change.

A troublesome feature at menopause, hot flashes have around a 70% prevalence in women living in the Western world, lingering for up to 10 years [Figure 2].[1],[2] When experiencing a hot flash, the woman has a feeling of intense warmth rising upwards from the chest area to the head, along with sweating, flushing, and chills. Occurring during the day and even more common; at night (generally referred to as night sweats), hot flashes are normally accompanied by sweating but do not have to be. Except the nuisance and discomfort of hot flashes other problems lurk in the hot flashes' backwaters such as mood disorders, psychological distress, and sleep disorders, negatively influencing social interaction and work, generally lowering the woman's quality of life.[3],[4] In the Chinese population only 15% of menopausal women seem to have troubles with hot flashes, a much lower proportion in the society.[5]
Figure 2: Hot flashes is a troublesome feature at menopause

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How can we approach the issues of hot flashes from the perspective of TCM? Broadly speaking, hot flashes and its clinical manifestations belong to perimenopausal and postmenopausal syndromes with a rather sudden decline in Kidney energy (capitalized to distinguish the Chinese view of these organs as focusing on their function). Classically, it has been defined as a Kidney-yin deficiency: hot flashes, red face, sweating, hot sensations in palms and soles, constipation, dryness of the mouth, ringing ears, insomnia, lumbar soreness, knee weakness, and red tongue. If yin is deficient, it cannot defend and hold back yang, and as a consequence, endogenous heat will disturb the body and the body's fluids cannot be kept well, thus the emergence of hot flashes.[6],[7]

In addition, Kidney essence is the origin of the female reproductive system and of both yin and yang. Thus, Kidney essence encompasses the whole foundation and congenital basis of a person, therefore, the body's entire functional and material roots. The woman's Kidney essence is affected and weakened when reaching perimenopause [Figure 3]. As the root of both yin and yang, consequently we would find many women with hot flashes presenting not only with yin deficiencies but also with Kidney yang deficiency symptoms; cold limbs aversion to cold, painful knees, apathy, easily sweating, incontinence, pale face, and pale tongue.[8],[9] One of the known dynamics of the body, is that if kidney yang cannot sufficiently support the spleen during the transformation and absorption function, there will be a lack of nutrients available to the body. Thus, when the spleen fails to support the body with adequate moisture and nutrients, the blood becomes deficient. The body then develops patterns of dry hair, brittle nails, vaginal dryness, dry cough, dry eyes, constipation, and anxiety resembling that of kidney yin deficiency symptoms. Moreover, showing a kidney yang deficiency, a woman's defensive qi gets weakened; this includes the body's opening and closing function, resulting in the leakage of body fluids, including sweating.
Figure 3: Traditional Chinese medicine kidney dynamics at perimenopause

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During the menopausal transition, these kidney deficiencies will involve and affect other viscera and systems of the body, including the Liver, Spleen, Heart, and Lungs.[6],[8]

Researching ancient Chinese medicinal literature concerning the understanding of perimenopausal hot flashes we find the pathogenesis is mainly “deficiency of Kidney qi,” “debility of thoroughfare and conception channels,” and “yin-yang disharmony.” The ancient classic on Chinese medicine, Huang Di Nei Jing (《黄帝内经》 Huangdi's Internal Classic), states that a woman in this time of her life is influenced by a decline in Kidney energy with other meridians and viscera involved. Huang Di Nei Jing Su Wen (《黄帝内经·素问》Huangdi's Internal Classic Basic Questions) states that “When the woman reaches the age of 49-year-old, the Kidney qi gradually declines, the tiangui (menstruation) gradually dries up, and the thoroughfare and conception vessels (CVs) no longer dominate a woman's energetic physiology. During this period, due to the influence of both the internal and external environment, such as the deficiency of yin and yang, or the changes of family and social groups, it easily leads to an imbalance of kidney yin and yang”. Huangdi's Internal Classic also mentions that “The Kidney is the foundation of nature”; and “When diseases of all the other viscera are too severe, they are certain to involve the Kidney.” Specifically, the imbalance of kidney yin and yang can easily affect other viscera (and meridians), while the disease or imbalance of other viscera will affect the Kidney. Thus disease at menopause will be rooted in the Kidney, often involving the Heart, Liver, Spleen, and other organs and channels. Consequently, a series of clinical manifestations including hot flashes will appear.[10]

The conception and governor vessels are energetically interesting representations of yin and yang. They are the two coupled yin-yang meridians that run along the central line of the body's front and back. They are two branches of the same source, both reaching the uterus. The GV connects the uterus with its branch; the CV internally originates in the uterus and therefore, connects the uterus to the kidney, heart, and brain.[11] They both externally originate at the perineum, the Huiyin point (CV 1), and both vessels reach the brain in their circuits; thus, together complete an orbit of yin and yang of the upper body.[12] In Qigong, the practice and positions should always be regulated to unblock the two meridians' free flow. Their circular rotation supports the whole body's qi and all the 12 yin and yang meridians. The fact that both are connected to the uterus area can liken this circuit to the Hypothalamic Pituitary Ovarian (HPO) axis, and possibly the Hypothalamic Pituitary Adrenal (HPA) axis (see below the yin-yang representation of the reproductive and adrenal endocrine systems). Ling Shu “Wu Yin Wu Wei” (《灵枢·五音五味》 Miraculous Pivot “Five Tones, Five Substances”) states that Tiangui, as a woman's menstrual blood (or menstrual water) is the essence of qi, so the Kidney essence is directly related to the CV, which “regulates the womb” and is the “foundation of health.”

Hot flashes pathogenesis from an allopathic medicinal perspective is rather complex. The dynamics mainly include estrogen withdrawal, luteinizing hormone decrease, serotonin (5-HT) receptor system disorder, reduction of endogenous opioid peptides, disruption of catecholamine release, and the changing function of the calcitonin gene-related peptide receptor.

Generally speaking, we find that there is a flawed mechanism when hot flashes emerge; the neuro-endocrine-immune system of the body is changed during the estrogen withdrawal stage during perimenopause. This affects the body's synthesis and secretion of a series of neurotransmitters and hormones; for instance, serotonin and norepinephrine and disrupting the HPO axis feedback loop [Figure 4] as well as interfering with the HPA axis.
Figure 4: The Hypothalamic-Pitutary-Ovarian axis feedback loop; in Western medical understanding a disruption of its dynamics is the main factor to cause hot flashes

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When estrogen levels fall in perimenopause, the hormonal feedback loop in the pituitary and hypothalamus malfunctions, creating several hormonal changes and imbalances in the body. The hypothalamus is the center in the brain that controls the body's core temperature. Novel studies have found a narrowing of the thermoregulatory center in the hypothalamus as one of the causes of hot flashes. This supposedly creates a narrowing of the temperature allowance, causing the body to react to any small temperature changes, internal or external. This sensitivity will cause a sudden impulse of heat release triggering a hot flashes.[13],[14],[15]

For decades, the understanding of the hot flashes' basic dynamics and mechanics has been somewhat simplified. Doctors and health practitioners readily attribute the nuisances of hot flashes to a decline in estrogen production, correlating it to vaginal dryness, dry skin, irritation, and sleep issues. Therefore, hormone replacement therapy (HRT) has been the first solution to tackle these problems, accounting for approximately 80% of doctors' prescriptions and treatment solutions in the Western world [Figure 5]. Even if HRT is effective with up to a 90% efficacy in reduction of the hot flashes, the medications come with serious health risks and discomfort, ranging from breast cancer to thromboembolic events to irregular bleeding and breast tenderness.[1],[16] An important point to remember here is that estrogen depletion is present in all menopausal women, but not all these women have hot flashes. While the drop in estrogen levels is a natural transitional occurrence at menopause, hot flashes are a symptom of imbalance, encompassing a wide range of different biological mechanisms.
Figure 5: Sweating at menopausal transition is to 80% treated by Hormone Replacement Therapy in the western world

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Bearing this in mind, it is both intriguing and of great utility to try and combine these two separate medical understandings of hot flash mechanisms into one streamlined approach. One way to look at it, is to focus on how the decline of estrogen and progesterone production by the ovaries influences a decline in essence within the reproductive system's yin and yang. As progesterone levels peak in the menstrual cycle, this corresponds to the yang phase in Kidney energy. Subsequently, estrogen levels peak during menstruation and correspond to the yin phase [Table 1]. Cessation of estrogen at menopause has the same clinical manifestations as a Kidney yin deficiency, but we should be careful and observe the whole picture of deficiencies and imbalances. First, yang deficiencies may be discovered, and recent studies on progesterone levels as influencing the Kidney yang, have suggested that they are a predictor of hot flashes.[17] Second, the neurotransmitter serotonin is influenced by estrogen, and is largely involved in deciding the magnitude of the thermoneutral zone within the hypothalamus. Serotonin can be seen as a yin factor, cooling the system. Third, norepinephrine, another neurotransmitter in the brain, excites the nervous system and narrow the thermoneutral zone. Norepinephrine can be viewed as a yang factor, heating the body. Lastly, the TCM Kidney represents a broader dynamic of the endocrine system (except the kidney-urinary system), where the dynamics of the adrenal glands are involved. The Yin function of the adrenal glands includes the body's buffer function, involving the secretion of glucocorticoids, acting like a stabilizing factor that the body uses to tolerate and fight stressors. These yin functions can be considered critical “hypo” functions of the body, which include the parasympathetic nervous system. Conversely, yang functions are the body's “hyper” functions used to excite and stimulate different systems and encompasses the secretion of adrenaline and noradrenaline from the adrenal glands. Adrenal functions also involve the pituitary and hypothalamus; therefore, the HPA axis is an intriguing mechanism to represent the TCM Kidney and its imbalances of yin and yang as the HPO axis.[11]
Table 1: Correspondence between the concept of yin yang and hormonal changes in the menstrual cycle

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Back to yesterday's small TCM workshop with the five perimenopausal women; four experienced troublesome hot flashes; two of them felt it seriously disturbed their sleep and quality of life. Approaching our workshops end, we agreed to check our tongues to find out who had red tongues suggesting heat in the body and a kidney yin deficiency. Graciously, one after the other showed their tongue and interestingly they were all pale, some very pale, and some just pale. Three women had teeth marks on the sides of their tongues and were slightly swollen, suggesting waek digestion and weak spleen function. This small assessment added valuable information to the observations made at menopause: perimenopausal women with hot flashes are often Spleen qi, yang, and blood deficient with symptoms of fatigue, sensitivity to stress, restlessness, and anxiety.

  Treatment Alternatives Top

How can we then approach all this and create a successful treatment? Generally, we can find a range of alternatives to HRT. Complementary and alternative medicine treatments at menopause have had much publicity over the last few decades. Black cohosh, phytoestrogen (for instance, soy), yoga, Qigong, and acupuncture have received much attention as possible remedies for reducing hot flashes [Figure 6].[18],[19] TCM, a >2000-year-old medicinal practice has had long-standing success in treating menopause in China. TCM applies various concepts and treatment strategies that, in addition to acupuncture, also include herbal medicine, moxibustion, massage (Tuina), cupping, Qigong, and food therapy to enhance health preservation and quality of life. The reported positive effects, holistic approach and safe treatment procedures attract midlife women to try TCM to relieve their conditions.
Figure 6: (a) There are many effective and safe ways to balance and strengthen the body to relieve hot flashes at perimenopause (b) there are many effective and safe ways to balance and strengthen the body to relieve hot flashes at perimenopause

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  Acupuncture Treatment Top

Acupuncture treatment is one of the most commonly used TCM methods for middle-aged women. Findings confirm that hot flashes are likely to be reduced by needling some classical points such as Guanyuan (CV4), Sanyinjiao (SP6), and Yinxi (HT6). Study designs and syndrome patterns have confounded results about optimal point selection.[20],[21],[22] Treatment designs in larger studies are often streamlined and point selection standardized to compare larger trial populations. One trial that applied a more individualized design was undertaken by a Norwegian research team.[7] The researchers found 50% of their participants to be Kidney yin deficient. In total, they acknowledged seven types of primary syndrome patterns in hot flash conditions, which also seem to be the general consensus among other sources.[6],[12],[23] In an Australian acupuncture trial in 2017, they reached the same portion of Kidney yin deficiency; 50% of the hot flash population might be predominantly yin deficient.[20]

To test the effect of TCM acupuncture as a treatment option for hot flashes, in 2018 we started a hot flash trial at the Shanghai municipal hospital of TCM. This trial and analyses were part of my master's thesis at Shanghai University of TCM. The trial “Regulating and Unblocking conception and governor vessels - Acupuncture Method in the Treatment of Hot flashes in Perimenopausal Women: A Randomized Controlled Trial” was completed in 2020.

  Design and Syndrome Patterns in Our Study Top

A total of 72 Chinese and international perimenopausal women with hot flashes, whom all had hot flashes >four times in 24 h, enrolled in the trial. They were treated with acupuncture twice per week, 30 min each session for six weeks; at the end of the trial, sixty-six patients had completed all recordings, treatments, and follow-ups required by the trial [Figure 7].
Figure 7: Our acupuncture trial at Shanghai municipal hospital of traditional Chinese medicine had 66 patients completing the treatment program

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We applied the strategy of two parallel groups; one acupuncture group and one control group (these women were on a waitlist and were given personal health support during the six weeks). Sham acupuncture had some less than satisfactory results in recent international hot flash studies; it was decided to skip the sham needling's uncertain factor.[18],[20],[23]

The requirements of our research study set by the university as well as time limitations had two implications. First, we had to choose a clear and standardized treatment method. Second, from the 72 women enrolled in the study, we were only able to carefully diagnose and track the progress of the syndromes in the first 19 patients. As the diagnostic patterns are valuable in a TCM treatment setting, I would like to share some of our findings.

After an initial TCM assessment, the 19 women's diagnostic patterns could be redefined as the treatment proceeded, due to the acupuncture in many cases affecting their hot flash situation. Below are the syndrome patterns presented in these women and the frequency and severity of the hot flashes they experienced at the start of the trial.

The analysis of the patterns at enrollment showed some interesting findings. Among the 19 patients, nine presented with yang deficiencies, ten patients had clear signs of yin deficiency, including those with Liver yang rising. Where yin was the predominant deficiency pattern, the women often had complimentary issues with Liver yang rising or Heart yin deficiency with hyperactivity and heat flaring up to disturb the brain. When Kidney yang was deficient, the Spleen's function was often affected in its transformation and transportation function. Liver qi stagnation was often found as a secondary pattern. Three women presented with stomach heat and a very tense and rigid upper gastric area and diaphragm. Hot flashes were emerging strongly, almost like a pain, from this area.

  A Treatment Strategy for Hot Flashes Top

At the start of our clinical trial, it was a challenge to determine how to target and balance such basic and profound yin and yang dynamics, accounting for the patients' hot flashes. There are systematic changes on both the physiological and biochemical levels, including the endocrine system, HPO, HPA axes, and the brain centers and neurotransmitters. As the treatment strategy should involve harmonizing basic yin and yang dynamics, the idea to treat the governor and CVs as part of the protocol developed.

Due to our time limits, our point selection was standardized. Our choice of points were:

Baihui (GV20), Yintang (GV29), Shenting (GV24), Guanyuan (CV4), Qihai (CV6), Zhongwan (CV12), Sanyinjiao (SP6), Taixi (KI3), Fuliu (KI7), Yinxi (HT6).

We did not want to choose points on the back such as BL23 (Kidney shu) or GV4 (Mingmen), as we would have to turn the patient over. Our chosen TCM acupuncture strategy was to link the lower abdomen, and reproductive areas applying the CV4 and CV6 points, to the governor meridian points Baihui and Yintang. Additionally, from TCM theories and current international knowledge of hot flash dynamics, our logic for the choice of points was a combination of three ideas:

  1. A basic yin-yang balance is disrupted. The governor and conception vessels are the seas of yin and yang meridians of the body. They both enter the uterus area and are also connected at the perineum, and the head, needling key points along these two meridians are fundamental nourishing yin and yang [Figure 8]. Regulating the governor and CVs can also indirectly unblock the GV to help supplement Kidney qi, which would always be tonified in perimenopausal issues. On the CV, we chose: Zhongwan (CV12), Qihai (CV6), and Guanyuan (CV4). Guanyuan (CV4) needle placement is directly on the CV and is represented as the place that stores blood. It is closely related to a woman's reproductive cycles and benefits endocrine regulation. CV4 is the Spleen, Liver, and Kidney meridians' meeting point that help nourish and regulate the body's yin aspects. CV6 is the sea of qi, and together with CV4, they strengthen the foundational qi of the body.[6],[12],[22] CV12 helps to relax and smooth the upper gastric area where many tensions and worries are held within hot flash women
  2. Link to the brain centers. The GV is a bridge that communicates with the brain directly. Nan Jing “Er shi Ba Nan” (《难经·二十八难》 Classic of Difficult Issues “The Twenty-eight Difficult Issue”) states that ” The governor originates from the transmission of the lower pole, runs in the spine, up to Fengfu and belongs to the brain.” Reaching the reproductive area and connecting with CV, the brain part of the meridian runs in the area of the pituitary and hypothalamus, which are the brain centers involved in thermoregulation. Seen from a TCM perspective, stimulating and regulating this meridian helps the HPO and adrenal axis function. We chose the Baihui (GV20), Shenting (GV24), and Yintang (GV29) points on the GV. These three points jointly regulate the GV in order to regulate the mind and tonify the Kidney, including the endocrine system. The Yintang point is referenced in ancient Chinese and Indian texts. It is closely connected to the pituitary gland, the primary gland of the endocrine system and to a person's intuition and balance of the two yin and yang forces[6],[12]
  3. Traditionally applied points for hot flashes and night sweats. Treating hot flashes should include points directly supplementing the Kidney and the yin aspect of a woman in order to nourish and calm the system, therefore helping to subdue yang. CV4, KI3, KI7, SP6, and HT6 have all been frequently used both traditionally in clinics and in international trials to reduce hot flashes.[20],[22],[24],[25] For CV4 see above. Fuliu (KI7) and Taixi(KI3) belong to the Shaoyin Kidney meridian of the foot, nourishing the Kidney and yin. Yinxi (HT6) belongs to the Shaoyin heart meridian of the hand, which helps treat steaming bone disorder and night sweating. It has the function of clearing heat deficiencies and gathering yin fluids, which are mainly used to treat yin deficiencies, night sweating, and hot flashes. Sanyinjiao (SP6) is the key point of fitness and good health and is located at the intersection of the foot's three yin meridians. Combining these points can balance qi, blood, yin, and yang functions as well as improve perimenopausal hot flashes.
Figure 8: The running course of the Conception and Governing meridians is creating an orbit of the upper body, connecting to the uterus as well as to the brain centers responsible for a balanced hormonal secretion

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In a standard clinical setting, an individual pattern differentiation should support this treatment protocol and points should be added flexibly to optimize the patient's treatment results, yielding a personalized medicinal approach to patient therapy. Moxa can be added as well to support the conditions related to the Spleen, Liver, and Heart when needed.

  Results and Discussion Top

What outcomes did our methods and treatment strategy have?

The results of this study showed that acupuncture therapy focused on regulating and unblocking the conception and governor vessels could effectively reduce both the frequency and severity of hot flashes in perimenopausal women [Figure 9]. The quality of life experienced by the women was also improved. The treatment proceeded without any adverse events.
Figure 9: After 6 weeks of acupuncture treatment both the frequency and severity of the women's hot flashes were reduced

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[Table 2] shows that the frequency of the hot flashes for the women having acupuncture treatment was reduced after six treatments and showed a continued reduction one month after the 12 treatments were completed [Figure 10]. This was found both compared to the waitlisted women and to the daily number of flashes they had at the start of the trial.
Table 2: Diagnostic patterns and baseline data in the 19 first enrolled hot flash Chinese and international women

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Figure 10: The frequency of the hot flashes for the women having acupuncture treatment

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In terms of the severity of the hot flashes, i.e., how strongly they experienced them, we found a similar positive effect of the acupuncture treatment. In the patients who experienced very intense and strong hot flashes that originated in their upper gastric area, the therapy was successful after four to five treatments. The women felt their upper gastric area beginning to soften, and the severity of their hot flashes decrease.

There was also an evident positive change in the participants' perceived quality of life during the six weeks of treatment.

The body houses a complex system of hormonal secretion and regulation mechanisms, and therefore the hot flashes can be addressed from numerous angles. We applied an acupuncture method focused on regulating and unblocking the conception and GVs, which corresponds well to TCM diagnostic patterns of hot flashes and to Western medical findings of the disruption in the body's HPO and HPA systems.

From our findings and supported by novel research, TCM acupuncture can confidently be used as a safe and efficient treatment method to support women going through perimenopause and help reduce troublesome hot flashes.

The main finding in this article researching perimenopausal hot flashes in women is that it is possible to reach a diagnosis utilizing both yin and yang deficiencies as the root cause that affects many visceral systems. Yin deficiency seems obvious as estrogen production, representing one of the body's yin substances, comes to an end. An important reminder here is that depleted estrogen levels are a natural occurrence in menopause, but not all women suffer from hot flashes. Different bodies handle this transformational stage differently. Therefore, we should search for other dysfunctions and imbalances. For instance, many women in midlife have developed yang deficiencies. We hope to have the time to individualize our treatment design more in the future. It will be an essential piece of information to follow the progress of every woman's unique pattern and be able to apply points individually after that.

Pictures by Anna Bogachko Holmblad and Eva-Britt Andersson, Artist. Thanks to A M Hellberg Moberg, freelance writer in London UK, for helping with the text.



Conflicts of interest


  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]

  [Table 1], [Table 2]


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