Mizaj (temperament) is one of the fundamental concepts of Unani system of medicine, diagnosis and line of management of any disease is based upon it. Every human being has been furnished with a specific mizaj through which organs and systems of an individual perform his functions properly [1]. Internal and external causes influences the human body leading to su’ mizaj (altered temperament) that ultimately inflict the whole body or a specific organ in the form of disease. The principle of management of disease is to correct the altered temperament. Therefore, before commencing any treatment, mizaj of a patient or organ has to be evaluated.

Unani scholars also inscribed that the human life is basically divisible into four age groups and each age group have their particular mizaj for example, mizaj is barid (cold) and yabis (dry) between 35 and 60 years age group and this period of life is known as sin al-kahulah/ sin al-ya’s (late adulthood). At this age, dynamic changes occurs in reproductive and nonproductive tissues and production of rutubat algariziya is decreased to such an extent that it is insufficient to maintain hararat al-gariziya (innate heat) and all the quwa (power) starts deteriorating [2]. In sin al-ya’s because of change in mizaj towards burudat (coldness), ihtibas al-tamth (amenorrhea) can occur naturally. Additionally, the production of dam (blood) is decreased from liver, whatever little is produced, tends to be towards coldness [3]. This leads to clinical manifestations associated with ihtibas al-tamth such as fatigue, loss of appetite, weight gain, hirsutism, headache, backache, neck pain, general myalgia, arthralgia, nervousness, anxiety, depression, and insomnia [3,4]. Ihtibas al-tamth is defined as absence of menstrual bleeding for more than 2 months or decrease in quantity [5,6] similarly defined in conventional system of medicine [7]. It may be primary (i.e., never menstruated) or secondary (i.e., attained menarche, amenorrhea more than three months).

Though in classical Unani sources, straight forward discussion of menopausal transition is not mentioned but its symptoms are mentioned under the heading of ihtibas al-tamth. In conventional medicine, menopausal transition encompasses a period of dynamic changes in reproductive and non-reproductive tissues [8]. Menopausal transition is a period when the endocrine, biological, and clinical features of approaching menopause begin and menstrual irregularities are the commonest initial marker. The biology underlying the transition to menopause includes central neuroendocrine changes as well as changes within the different organs of the body [9]. It may be viewed as a problematic period of menstrual, emotional and physiological changes. The menopausal transition may begin as early as fourth decade (late 30s) and may vary between 2 to 8 years in length [10]. Women also experiences higher prevalence of somatic and psychological symptoms [11]. Menopausal transition has been divided into an early and late phase by Soules and other at the Stages of Reproductive Aging Workshop (STRAW) held in July, 2001 [12]. Early transition: changes in cycle length of ≥ 7 days either direction observed for at least two consecutive cycles or 60 days amenorrhea. Late transition: 90 days to 11 months amenorrhea. Menopausal transition is known to play major role in the etiology of symptoms such as hot flashes, night sweats, menstrual problems and vulvovaginal atrophy, mood changes, sleep disturbances and sexual dysfunction are also commonly reported and may be attributable to the hormonal aberrations experienced during the transition [13]. The menopausal and the years of life spent on the menopausal state bring with them issues related to both quality of life and disease prevention and management [14]. Hence, mizaj of the patient in this disease should be assessed so that appropriate treatment can be given. Till date none of the studies have assessed the mizaj in menopausal transition symptoms. Hence, this pilot study was planned to determine the mizaj in menopausal transition women.

A prospective, single center pilot study was carried out in the National Institute of Unani medicine (NIUM), Bangalore, India between April 2013 and January 2014. Written informed consent was obtained from each patient before entering into the study. A total of 60 menopausal transition women aged ≥ 35 presenting with early and/or late transition menopausal transition symptoms for at least two months were included. Women with undiagnosed vaginal bleeding, malignancies, surgical menopause (bilateral oophorectomy), uncontrolled hypertension, uncontrolled diabetes mellitus, and thyroid dysfunction were excluded.

Patients were interrogated and detailed history, physical and gynecological examination and menopausal rating scale questionnaire was filled. Kuppuswamy’s socioeconomic scale was used for socioeconomic status evaluation. Menstrual calendar was used to assess menstrual regularity and amount of flow. For exclusion of general diseases routine investigations were carried out. Thyroid profile and ultra sonography of abdomen were carried out to exclude, thyroid dysfunction, uterine fibroid, and malignancy respectively.

The patient’s initial severity of symptoms was evaluated using the validated health-related quality of life (HRQoL) questionnaire, menopause rating scale (MRS). Menopause rating scale consisted of 11 items assessing menopausal symptoms and a 5-point rating scale permits the patient to describe the perceived severity of complaints graded from 0-4, (0= not present), (1=mild), (2=moderate), (3=severe), (4=very severe) by checking the appropriate box. For the present study, the MRS English version was used. The composite score for each of the sub-scales is based on adding up the scores of the items of the respective dimension scores [15]. The total score ranges from 0 to 44. Scores ranging from 0–4, 5–8, 9–15, and 16+ were used to rate the perceived menopausal symptoms as none/minimal, mild, moderate, and severe respectively [16]. The total MRS and subscale scores were calculated. The mizaj was assessed by alamate su’ mizaj (clinical features of altered temperament) of body and ghalaba-i-akhlat (dominance of humour) and dalaele amzaj al- rahim (clinical features of temperament of uterus) as described in the traditional Unani literature (Table 1) [17]. Signs and symptoms were scored on rating scale 4 through 1 for alamate su’ mizaj, ghalaba-i- akhlat and dalaele amzaj al-rahim. Total score of each patient was added up and the inferences for type of su’ mizaj was deducted based on equal interval scale developed from total score for the questionnaire. The reliability of the questionnaire was found to be 0.87 for split half reliability.

Table 1: Alamate Su’ Mizaj, Ghalaba-i-Akhlat and Dalalae Amzaja al-Rahim.

Data analysis

Statistical software: The Statistical software Graph Pad Instat version 3.00 for window (Graph Pad Software, San Diego, Calif, USA) was used for the analysis of the data and Microsoft word and Excel have been used to generate graphs, Tables etc.

Statistical analysis

Descriptive analysis was performed by means of the frequencies of the category variables and measurements of the position and dispersion of the continuous variables. Results on continuous measurements were presented on Mean ± SD (Min-Max) and results on categorical measurements were presented in number (%).

A total number of 123 patients completed pre-baseline screening in which 60 patients met the criteria. Remaining patients (n=63) were excluded from the study because of different reasons. Thirty patients declined to participate and 33 patients were excluded [thyroid disease (n=10); uncontrolled hypertension and diabetes (n=11) and pelvic pathology (n=12).

Baseline characteristics

The baseline variables (age, diet, socio-economic status, duration of illness, BMI, gynecological and obstetrical history, MRS and subscale scoring) are summarized in Table 2.

Table 2: Baseline characteristics.

Early and late menopausal transition and menstrual irregularity: Early and late menopausal transition was noted in 22 (36.67%) and 38 (63.33%) patients respectively. It was noted that all 58 (93.33%) patients had qillat-i-tamth (hypomenorrhea) or ihtibas al-tamth.

Mizaj

Of 60 patients, 41 (68.33%), 15(25%) and 4(6.67%) patients had barid (cold), harr (hot) and yabis (dry) su’ mizaj respectively. All patients had ghalaba-al-sawda (dominance of black bile humour). Of 60 patients, 55(91.67%), and 3(5) patients had clinical features of burudat al-rahim (coldness of uterus) and hararat al-rahim (hotness of uterus), respectively and one patient each had symptoms of rutubat al-rahim (wetness of uterus) and yabusate al-rahim (dryness of uterus). Distribution of patients according to age and su’ mizaj is summarized in Table 3.

Table 3: Distribution of patients according to age and Su’ Mizaj (altered temperament).

Menopausal transition symptoms

The menopausal transition symptoms in each of the 11 individual symptoms (Hot flushes, heart discomfort, sleep problem, muscles and joint problems, depression, irritability, anxiety, physical and mental exhaustion, sexual problems, bladder problems and dryness of vagina) of MRS are summarized in Table 4. The distribution of patients according to su’mizaj and severity of menopausal transition symptoms are summarized in Table 5.

Table 4: Menopausal transition symptoms.

Table 5: Menopausal transition symptoms and Su’ Mizaj (altered temperament) according to severity.

Menopausal transition symptoms were present from the age of 35 years in the present study however, maximum number of patients (n=41, 64.9%) were between 41 and 50 years. Mean age of the patients in the present study was 43.83 ± 4.00 ranging from 35-52 years. IbnSina states natural ihtibas al-tamth may occasionally occur early at the age of 35 otherwise 40-50 years. He also mentioned that after cessation of menstruation women resembles to men and milk discharge from breast is observed, which indicates that woman as reached the age of sin-alyas [17]. Ismail Jurjani, Sabit bin Qurah and Bagdadi observed that cessation of menstruation is between the age of 35-60 years [3,18,19] and Zakriaya Razi stated that menstruation stops at the age of 40-60 years [4]. Siobán et al. reported 45.5 years median age of entry into the transition and 4.8 years duration for transition [20]. Freeman et al. reported 45.7 ± 3.6 years (range 39–53 years) mean age for menopausal transition; 47% remained premenopausal, and 53% were in the menopausal transition stages or postmenopausal [21]. Chronological age is a less sensitive indicator of reproductive aging due to relatively wide age range (42–58 years) of menopause though it is frequently used as a marker of the transition [21]. The mean age of inception of menstrual changes is 47.5 years, so that the mean duration of the transition is 3.8 years [22].

The mean BMI was 28.72 ± 5.34 kg/m². Mean BMI increased with increasing age. The mean waist/hip ratio was 0.949 ± 0.04. Earlier study reported no association with waist or hip circumference or their ratio or the trajectory variable [23]. Their hormone status was quite different when compared to women undergoing menopause transition (MT) [24].

Early and late menopausal transition and menstrual irregularity: Early and late menopausal transition was noted in 22 (36.67%) and 38 (63.33%) patients respectively. It was noted that all 58 (93.33%) patients had qillat-i-tamth (oligomenorrhea) or ihtibas al-tamth (amenorrhea).

Ibn Sina states that cessation of menstruation in woman occurs at age of sin-al-yaas [17]. Further Unani scholars, discuss that sin alkahulah (middle age) is period ranging from forty to sixty years. In this period of life, quantity of rutubat al-ghariziyah is lesser than the quantity required for the preservation of hararat al-ghariziyah or bodily metabolism. But there is no domination of rutubat al-gharibah (abnormal metabolic compounds). In this period the powers and faculties begins to deteriorate but there is no marked dissolution. The mizaj at this period is barid and yabis. Baghdadi opined that tahleel (dissolution) of akhlat (humour) in women is less, as they do lesser physical activity and vessels are narrower than men, therefore, there is accumulation of akhlat and fuzla in the body. To maintain homeostasis, body eliminate this fuzla (waste product) through haiz (menstruation), as process of tabayi istefragh (physiological elimination). Hence, when ihtibas al-tamth (amenorrhea) occurs, it leads to different kind of disorders [19]. Unani scholars state at this age, mizaj of the woman changes more towards burudat. The production of blood in liver gets decreased, whatsoever is produced that too declines towards coldness [3,17]. Hence, the causes of ihtibas al-tamth at this age may be burudat al-rahim or ghalaba al-burudat (dominance of coldness), sudda urooq al-rahim (closer of uterus or its vessels due to obstruction), or increased viscosity of blood [4,17]. In ghalaba al-burudat, ghaleez akhlat (viscos humour) mixes in the blood that leads to symptoms such as weakness of the body, increase frequency of micturition, su’ al-hazam etc. [25].

Many women in the present study suffered from menstrual problems, some with irregular menstrual cycles with increase duration of menstrual cycle. Though menstrual irregularities are not listed and scored on the MRS scale, they are certainly one of the first and major worry of women in perimenopause. The onset of the menopausal transition is marked by changes in the menstrual cycle and in the duration or amount of menstrual flow. Consequently, cycles are missed, but the pattern is often unpredictable early in the menopausal transition [26]. In earlier study, it was noted that common pattern (where menstrual cycle lengths increase as menopause approached), about 25 per cent of women appeared to have no or minimal change in menstrual cycle variability or mean length before their final menstrual period (FMP). In SWAN, longer menstrual cycle lengths and more variable menstrual cycles were associated with a shorter time to FMP [20]. Few studies have reported hormone changes in relation to changes in menstrual cycle characteristics, such as the first self-reported change in the amount of menstrual flow, in the frequency of menstruation, or in the combination of changes in flow and frequency, an approach that has been adopted in the Melbourne Women’s Midlife Health Project [9].

Menopause rating scale (MRS) and menopausal transition symptoms

The total MRS mean score was 29.53 ± 5.11 and all 60 (100%) patients had total MRS Score 16+, which shows that women HRQOL was severely affected. The somatic, psychological and urogenital symptoms mean score are summarized in Table 2.

Menopausal transition symptoms in each of the 11 individual symptoms of MRS showed that all patients had most of the symptoms in the present study, which validates the claim of Unani scholars. Unani scholars mentioned that other symptoms of su’ mizaj barid (cold altered temperament) are also noticed in ihtibas al-tamth caused by ghalaba al-burudat (dominance of coldness) such as frequency of micturition and depression [27]. Further, they surmised that ihtibas al-tamth also leads to awarizate (complications) such as distortion of body figure, ikhtinaq al-rahim (hysteria) [19] depression, irritability, aneroxia increase thirst, heart becomes weak that leads to khafkan (palpitation), suda (headache) and heaviness of head, pain increases, stomach becomes weak leading to indigestion [19], anxiety, body becomes weak leading to fatigue, heaviness of body, dysuria, increase frequency of micturition etc. Occasionally in ihtibas al-tamth, women develop hair growth on face and upper lip, indicating that women had attained menopause [17,19]. Unani scholars discussed that above mentioned symptoms develops because of musharikat al-rahim (involvement of uterus) with other organs of the body. Bukharat (gases like substances) from the urooq al- rahim (uterine vessels) pass through the blood to the other organs of the body such as brain, head, stomach, musculoskeletal, heart etc., causing aforementioned symptoms [19]. In conventional medicine, it is mentioned that symptoms experience varies between individuals and throughout the transition. Most symptoms are reported during the perimenopause. These can be due to estrogen excess (migraine, nausea, breast tenderness, menorrhagia, shorter cycle length) or deficiency (vasomotor symptoms and vaginal dryness) and commonly fluctuation, reflecting the fundamental hormonal instability during these years. It is mentioned that estrogens modify synthesis, release, and metabolism of many neurotransmitters such as serotonin, dopamine, nor-adrenaline, acetylcholine, and melatonin neuropeptides including β-endorphin, which modulate the activity of hypothalamic centers and the limbic system. Fluctuating levels of sex steroids, chiefly estrogen, result in altered function of the hypothalamus and limbic system and in this manner the regulation of mood, psychological well-being, thermoregulation and vasomotor stability, and many other functions occur. Estrogen withdrawal in menopausal women also results in considerably lowers blood serotonin levels. Low blood estrogen levels are also related with up-regulation of certain serotonin receptors (5-HT2A) in the hypothalamus that are supposed to be involved in thermogenesis [28].

The strength of the present study was till date none of the studies, have evaluated mizaj in women with menopausal transition symptoms. Further, somatic, psychological and urogenital symptoms of menopausal transition were evaluated using the validated Health- Related Quality of Life (HRQoL) questionnaire, Menopause Rating Scale (MRS). The Menopause Rating Scale (MRS) was a valuable tool in determining the menopausal transition symptoms in patients.

Though current findings are important, the limitation of this study was test and re-test reliability of parameters used for assessments of mizaj has been not carried out. Hence, further it is recommended to validate the mizaj parameters in larger sample size, so that these parameters can be used for clinical assessment of different diseases.

This pilot study validates the claim of Unani scholars that su’ mizaj burudat and ghalaba-i-khilt sawda is seen in women with menopausal transition symptoms.

Authors are thankful to the participants for their cooperation and give valuable time to complete this study. Authors are also thankful to the Director, NIUM for providing all facilities in the Institute.