EVALUATION OF INFLAMMATORY AND IMMUNOLOGIC

RESPONSES IN MENOPAUSAL HYPERTENSIVE PATIENTS IN

EKITI-STATE

BY
OWOSENI MICHAEL AKINTUNJI
[Link]. (IWO)

A PROJECT SUBMITTED IN PARTIAL FULFILMENT OF THE

REQUIREMENT FOR THE AWARD OF THE DEGREE OF
MASTER OF SCIENCE ([Link].) IN BIOCHEMISTRY.
FACULTY OF SCIENCE, EKITI STATE UNIVERSITY,
ADO EKITI, EKITI STATE.

SUPERVISOR
PROF. (MRS) M.F. ASAOLU
 CHAPTER ONE
INTRODUCTION
1.1 BACKGROUND OF STUDY
Globally, hypertension is the primary cause of cardiovascular disease and early mortality.
Over the past forty years, the global mean blood pressure (BP) has either been steady or slightly
dropped due to the widespread use of antihypertensive medicines (Mills et al., 2020). One of the
issues with public health that affects people everywhere, including Indonesia, is hypertension.
Hypertension is a chronic rise in both the diastolic and systolic blood pressure brought on by heart
and blood vessel problems. Because people with hypertension are unable to feel its symptoms, the
condition is frequently referred to as the silent killer. After TB and stroke, hypertension ranks third
in terms of causes of mortality in Indonesia, making for 6.8% of all causes of death across all age
groups (Devita, 2022). When the diastolic blood pressure exceeds 80mmHg and the systolic blood
pressure exceeds 120mmHg, it is commonly referred to as hypertension (Syah et al., 2020).

The understanding of the circulatory system that stems from the work of physician William
Harvey (1578-1657), who detailed blood circulation in his book De motu cordis, is where the
contemporary history of hypertension begins. In 1733, English clergyman Stephen Hales reported
the first blood pressure reading (Kotchen, 2011). Among the first people to describe what would
later be known as hypertension were Thomas Young in 1808 and Richard Bright in particular in
1836 (Kotchen, 2011). Kidney illness during this time was commonly referred to as Bright's
disease since Bright discovered a connection between heart hypertrophy and the condition. George
Johnson proposed in 1850 that the thicker blood vessels in the kidneys of patients with Bright's
disease could be an adaptation to high blood pressure (Johnson, 1850).

Based on pathological data, William Senhouse Kirkes in 1855 and Ludwig Traube in 1856
also suggested that increased pressure might be the cause of the link between left ventricular
hypertrophy and renal impairment in Bright's illness (Cameron and Hicks, 2000). Samuel Wilks
noted that diseased arteries and left ventricular hypertrophy were not always linked to kidney
disease (Cameron et al., 1996), suggesting that high blood pressure could occur in individuals with
healthy kidneys. Frederick Akbar Mahomed used a sphygmograph in 1874 to record the first case
of elevated blood pressure in a person without kidney [Link] Clifford Allbutt adopted the word
"hyperpiesia" to refer to the generalized circulatory disorder that is hypertensive disease (Laragh
and Brenner, 1995).

However, Scipione Riva-Rocci's development of the cuff-based sphygmomanometer in

1896[9] marked the official beginning of hypertension as a medical condition by enabling blood
pressure measurement in a clinical setting. By describing the Korotkoff sounds that are audible
when the sphygmomanometer cuff is deflated and the artery is auscultated with a stethoscope,
Nikolai Korotkoff enhanced the procedure in 1905 (Kotchen, 2011). The tracking of consecutive
blood pressure readings was improved even more in 1981 when Donal Nunn created a completely
automated, accurate oscillometric sphygmomanometer (Kusum et al., 2019).

Due to an increase in life expectancy, menopause which is defined as the cessation of

menstruation due to the reduction of ovarian follicular activity is a phenomenon that is becoming
more and more concerning. It is known to decline in the late 30s and to completely stop in the
early 50s for most women (Goodman et al., 2011). By 2030, 1.2 billion postmenopausal women
are predicted to exist globally (Afshari et al., 2020). Menopausal transition and peri-menopause
are terms that are interchangeable (Stanzel et al., 2022). Menopausal transition, the time when
ovarian function changes from being fertile to being infertile, is a normal and unavoidable
transformation that affects all women (Shakila et al., 2014).

Despite the fact that menopause is thought to be a universal condition, women's

experiences with the menopausal transition are treated differently by them as a result of
sociocultural conventions (Bahri and Latifnejad, 2020). Meleis (Meleis, 2010) argues that
menopause is an experience that is concealed by the patriarchal cultural backdrop, leading women
to prioritize the interests of their families over their own, including their health, and as a result, the
menopausal transition becomes invisible. Due to deeply ingrained cultural and traditional ideas,
women use a passive approach to manage menopausal transition symptoms (Bahri et al., 2017).

Menopause, however, can cause incredibly unpleasant physical symptoms, including

vaginal mucosa atrophy that can result in vaginitis, pruritus, dyspareunia, and stenosis;
genitourinary atrophy that can cause urethritis, dysuria, urinary incontinence, and frequent
urination; recurrent urinary tract infections; and vasomotor symptoms like hot flashes and night
sweats. In addition to the gynecological health issues brought on by lower estrogen levels,
menopausal women experience mental shifts such anxiety, sadness, fear of being sick,
hypersensitivity, and irritability, as well as weariness and weight gain (Dutta et al., 2012).
Menopausal symptoms can be managed by women by "natural" means, primarily non-
pharmacological techniques like diet, exercise, and herbal remedies for hot flashes (Cifcili et al.,
2009).

Moreover, osteoporosis and cardiovascular disease are more common after menopause
(Ilankoon et al., 2021). Despite the fact that pharmaceutical approaches, such hormone
replacement therapy (HRT), are frequently recommended for the management of menopausal
acute symptoms, such as hot flashes, vaginal dryness, nocturnal sweats, and mood changes
(Palihawadana and Morris, 2015). However, Since the first randomised trials of HT in older
postmenopausal women were published ten years ago, its clinical prescribing has drastically
decreased (Hulley et al., 1998). In secondary prevention, HT was found to cause more harm than
benefit when compared to placebo. Even in primary prevention studies conducted as part of the
Women's Health Initiative (WHI), HT was found to have detrimental effects on the cardiovascular
system in women between the ages of 50 and 79 (Maas and Franke, 2009).

1.2 SIGNIFICANCE OF THE STUDY

Hypertension, is a chronic medical disorder characterized by a continuously raised blood

pressure in the arteries (Naish, 2014). Compared to age-matched males, premenopausal women
have lower blood pressure (BP), and as they age, women are more likely than men to develop
hypertension (Martins et al., 2001). These results imply that sex or gender hormones play a
significant influence in hypertension. This study is expected to provide information on the
association between serum inflammatory biomarkers and risk of hypertension in menopausal
women in Ekiti-State.

1.3 AIM AND OBJECTIVES

The aim of this study is to assess the inflammatory and immunologic indicators in peri and
post-menopausal hypertensive patients.

The Objectives of this study are to;

i. estimate the concentrations of interleukin 6 (IL-6), Interleukin 17 (IL-17), interleukin 2

(IL-2), interleukin 4, interleukin 3, interleukin 8, interleukin 10, adiponectin, leptin and
 Tumor Necrosis factor-alpha (TNF-alpha) as biomarkers of inflammation in pre and post-
menopausal hypertensive patients;
ii. assess the serological test by determining the concentration of the immunoglobulins M
(IgM), immunoglobulin A (IgA) and immunoglobulin G (IgG) in the blood sample of pre
and post-menopausal hypertensive patients;
iii. estimate the concentration of C-reactive protein (CRP) to know the state of the immune
system and
iv. determine the concentrations of hormones estrogen, follicle stimulating hormone (FSH),
estradiol, inhibin and luteinizing hormone in the serum sample of pre and post-
menopausal hypertensive patients.
 CHAPTER TWO
LITERATURE REVIEW
2.1 HYPERTENSION
High blood pressure, or hypertension, is a chronic medical disorder characterized by a
continuously raised blood pressure in the arteries (Naish, 2014). Typically, high blood pressure is
asymptomatic (CDC, 2016). Nonetheless, it poses a significant risk for peripheral arterial disease,
dementia, atrial fibrillation, heart failure, stroke, chronic renal disease, and peripheral vascular
disease (Lackland and Weber, 2015). Globally, one of the main causes of premature death is
hypertension (WHO, 2012)

Primary (or essential) hypertension and secondary hypertension are two categories for high
blood pressure (Poulter, 2015). Most cases (between 90 and 95 percent) are primary, which is
high blood pressure brought on by a non-specific lifestyle and hereditary factors (Carretero and
Oparil, 2000). Lifestyle factors that raise the risk include eating too much salt, being overweight,
smoking, not exercising, and drinking alcohol (Poulter, 2015). The other 5–10% of instances are
classified as secondary hypertension, which is high blood pressure brought on by an obvious
reason, such as the use of birth control pills, kidney artery narrowing, chronic kidney disease, or
an endocrine problem (Poulter, 2015).

The diastolic (lower reading) and systolic (high reading) blood pressure readings are used
to categorize blood pressure (CDC, 2016). Most persons have normal resting blood pressure,
which ranges from 60 to 80 mmHg diastolic and 100 to 130 mmHg systolic (Whelton et al., 2018).
When an adult's resting blood pressure consistently remains at or above 130/80 or 140/90 mmHg,
most likely they have high blood pressure (Whelton et al., 2018). For children, other numbers
apply (James et al., 2014). When compared to office-based blood pressure testing, 24-hour
ambulatory blood pressure monitoring seems to be more accurate (Poulter, 2015). Diabetics are
about twice as likely to have hypertension (Petrie et al., 2018).

2.1.1 SIGNS AND SYMPTOMS OF HYPERTENSION

Rarely does hypertension have symptoms, and the only ways to diagnose it are either
through a health check or by visiting the doctor for a different issue. A few symptoms of high
blood pressure include headaches (especially in the morning and in the back of the head), dizziness,
lightheadedness, tinnitus (a buzzing or hissing sound in the ears), blurred vision, and fainting spells
(Fisher, 2005). Nonetheless, rather than being directly linked to high blood pressure, these
symptoms may also be due to related worry (Marshall et al., 2012). Upon physical examination,
ophthalmoscopy-observed alterations in the ocular fundus may be linked to hypertension (Wong
and Mitchell, 2007). Grades I through IV indicate the severity of the alterations characteristic of
hypertensive retinopathy; it may be challenging to distinguish between grades I and II (Wong and
Mitchell, 2007). There is a general correlation between the duration or severity of hypertension
and the degree of retinopathy (Fisher, 2005).

2.1.2 CAUSES OF HYPERTENSION

[Link] PRIMARY HYPERTENSION: Essential hypertension, which is the type of hypertension

that by definition has no discernible secondary etiology, is also referred to as primary hypertension
or idiopathic hypertension (John and Guyton, 2011). It is the most prevalent kind, accounting for
85% of cases of hypertension (Ferri, 2012). The remaining fifteen percent comes from a variety of
secondary hypertension sources (Ferri, 2012). Primary hypertension is most likely inherited and
results from a combination of genetic and environmental factors. Essential hypertension is more
common as people age, and those who had moderately high blood pressure when they were
younger are more likely to develop hypertension later in life. The risk of cerebral, cardiac, and
renal problems can all be elevated by hypertension (Messerli et al., 2007).

By definition, essential hypertension has no identifiable cause, Nonetheless, a number of

risk factors have been found which include;

1. Genetic Variation: An individual is more likely to acquire hypertension if they have a

personal family history of the condition (Fauci et al., 2008).
Studies linking genes to hypertension have looked at more than 50 genes, and the list is
still expanding. Kim et al. conducted considerable research on the angiotensinogen (AGT) gene,
which is one of these genes. They demonstrated that an increase in AGT raises blood pressure,
which may lead to hypertension (Dickson and Sigmund, 2006). Single variant testing has
demonstrated that SNPs were enriched for variants linked to renal function, coronary heart disease,
type 2 diabetes, and obesity in previously reported GWAS, indicating a role for genetic loci related
to blood pressure in cardiovascular outcomes (Genet, 2015). Investigations assessing ambulatory
blood pressure have included twins; the results of these investigations have indicated a significant
hereditary component to essential hypertension (Dickson and Sigmund, 2006).
Clinical investigations in human populations and animal studies have produced data that is
supportive. Most of these research lends credence to the idea that the inheritance is likely
multifactorial or that increased blood pressure is one of the phenotypic manifestations of several
distinct genetic abnormalities. Nevertheless, the current understanding of the genetic effect on
hypertension is incomplete. It is thought that establishing a connection between distinct genomic
variants and symptoms associated with hypertension might provide conclusive proof of heredity
(Kotchen et al., 2000). Another theory holds that Mendelian inheritance of single gene mutations
might result in hypertension (Williams, 2006).
2. Unhealthy Diet: One established risk factor for hypertension is a poor diet, which includes
consuming an excessive amount of harmful food. It is advised to follow a balanced diet for both
prevention and management (Mills et al., 2020).
Excessive salt intake for example falls under this category. The critical hypertensive
population responds to sodium intake in around one-third of cases (Weinberger, 1996). Blood
volume will increase as a result of fluids moving through the blood vessels by osmosis when salt
intake surpasses the body's ability to eliminate it through the kidneys. As a result, the cardiac
output increases and the arterial pressure rises. To counteract this, local auto regulatory
mechanisms raise the vascular resistance to blood flow, which keeps the capillary blood vessels'
normal pressure constant. Urinary sodium excretion rises in response to high sodium chloride
consumption, however this greater salt excretion is maintained at the price of elevated arterial
blood pressure (Fauci et al., 2008).
3. Aging: When linked to a western diet and lifestyle, hypertension can also be age-related;
in this scenario, it is probably complex (Carrera-Bastos et al., 2011). A plausible explanation might
be a decrease in vascular compliance as a result of the arteries being more rigid. Isolated systolic
hypertension with a wider pulse pressure may cause this to worsen. Aging is associated with a
reduction in glomerular filtration rate, which lowers salt excretion efficiency. This decline in
sodium excretion efficiency may be linked to the development of certain disorders such capillary
rarefaction and renal microvascular disease. Renal microvascular dysfunction appears to be a
major mechanism for causing salt-sensitive hypertension, according to experimental data (Kosugi
et al., 2009).
 4. Obesity: When compared to a person of normal weight, obesity can raise the risk of
hypertension by five times, and excess weight is responsible for up to two thirds of instances of
hypertension (Haslam, 2005). Over 85% of instances involve people whose body mass index
(BMI) is higher than 25 (Haslam, 2005). Using data from clinical and animal investigations, a
clear connection between obesity and hypertension has been established. Numerous processes
have been identified as probable causes of obesity-induced hypertension. These processes include
the renin-angiotensin-aldosterone system and the sympathetic nervous system activation
(Rahmouni et al., 2005).
5. Diabetes: Hypertension can also be caused by Insulin resistance and/or hyperinsulinemia,
which are components of syndrome X, or the metabolic syndrome. Insulin is a
polypeptide hormone secreted by cells in the islets of Langerhans, which are contained throughout
the pancreas. Its main purpose is to regulate the levels of glucose in the
body antagonistically with glucagon through negative feedback loops. Insulin also exhibits
vasodilatory properties. In normotensive individuals, insulin may stimulate sympathetic activity
without elevating mean arterial pressure. However, in more extreme conditions such as that of
the metabolic syndrome, the increased sympathetic neural activity may over-ride the vasodilatory
effects of insulin.
According to recent research, obesity activates the renin-angiotensin system (RAS) in
adipose tissue, which increases the risk of hypertension (Hasegawa and Komuro, 2009) and said
that either one of the two might induce the other by connecting the renin-angiotensin system and
insulin resistance (Saitoh, 2009).

6. Lack of Exercise: Frequent exercise lowers blood pressure. To help avoid hypertension,
the UK National Health Service recommends 150 minutes (2 hours and 30 minutes) of moderate-
intensity aerobic exercise each week (Sasi and Sugathan, 2021).

[Link] SECONDARY HYPERTENSION: Secondary hypertension, sometimes known as

inessential hypertension less frequently, is a kind of hypertension that is, by definition, brought on
by a main cause that can be identified (O’brien, 2010). It affects just 5–10% of people with
hypertension, which is far less prevalent than the other form, known as essential hypertension.
Tumors, renal problems, and endocrine disorders are only a few of its numerous causes. It may
also be a side effect of a lot of drugs.
 1. Kidney Disease: Kidney disease is a well-known cause of secondary hypertension. This
includes conditions like polycystic kidney disease (PKD), a hereditary kidney illness marked by
numerous cysts in both kidneys (hence the term "polycystic"). Rarely, these conditions can also
harm the liver, pancreas, brain, and pancreas (Ecder and Schrier, 2009). It can be either autosomal
dominant or autosomal recessive; the former is more frequent and is characterized by bilaterally
enlarged kidneys with many cysts, increasing cyst formation, and the contemporaneous onset of
hypertension, chronic kidney disease, and kidney discomfort (Chapman, 2008) or chronic
glomerulonephritis, a condition marked by inflammation of the kidney's tiny blood capillaries,
known as glomeruli (Licht and Fremeaux-Bacchi, 2009).
Diseases affecting the renal arteries that supply the kidneys might also result in
hypertension. Renovascular hypertension is the term for this condition; it is believed that the renin-
angiotensin system is activated by reduced renal tissue perfusion brought on by stenosis of a major
or branch renal artery (Voiculescu and Rump, 2009).
Certain kidney malignancies can also result in hypertension. In a young patient with
hypertension, renal cell carcinoma, Wilms' tumor, and juxtaglomerular cell tumor are among the
possible diagnoses for a kidney tumor, all of which have the ability to manufacture renin (Méndez,
2011).
2. Endocrine Disorders: Example of secondary hypertension that results from endocrine
disorder is called neurogenic hypertension. Increased norepinephrine and adrenaline release,
which stimulates vasoconstriction, as a result of long-term, high sympathetic nervous system,
adrenal gland, and sympathoadrenal system activity. The precise mechanism at play is the
increased production of norepinephrine and epinephrine, sometimes known as "stress hormones,"
which narrow blood vessels and enhance cardiac output. Since the fundamental cause of their
hypertension is not treated, people with neurogenic hypertension do not react well to diuretic
therapy (Mann, 2003).
3. Medication Side Effects: Hypertension can be brought on by some drugs, such as steroids
and NSAIDs (ibuprofen/motrin) (White, 2009). Additional drugs include some antidepressants
(like venlafaxine), estrogens (such those in oral contraceptives with strong estrogenic action),
buspirone, carbamazepine, bromocriptine, clozapine, and cyclosporine (Chobanian et al., 2003).
Rebound hypertension is the term used to describe high blood pressure that occurs when different
antihypertensive drugs are abruptly stopped (Robertson, 1997). Blood pressures higher than before
the drug was started may be the consequence of the rises in blood pressure. A hypertensive
emergency may arise from rebound hypertension, depending on how severe the rise in blood
pressure is. By gradually lowering the dose (sometimes referred to as "dose tapering"), one can
prevent rebound hypertension by allowing the body adequate time to acclimate to the dose
reduction. Among the drugs frequently used to treat rebound hypertension include centrally acting
antihypertensive medications, such as clonidine (Van Zwieten et al., 1984) and methyl-dopa
(Lawrence, 2010).
2.1.3 DIAGNOSIS OF HYPERTENSION
Using an appropriate blood pressure measuring technique is crucial for making an accurate
diagnosis of hypertension (Viera, 2017). Inaccurate blood pressure readings can vary by as much
as 10 mmHg due to typical improper measuring techniques, which can result in incorrect
hypertension diagnosis and categorization (Viera, 2017). The proper approach for measuring
blood pressure comprises many stages. In order to take a blood pressure reading correctly, the
subject must sit still for at least five minutes. After that, a properly fitting blood pressure cuff
must be applied to the subject's naked upper arm (Viera, 2017).
The individual sitting should have their legs straight, their feet flat on the floor, and their
back supported (Viera, 2017). During the process of taking their blood pressure, the individual
being measured should remain still and silent (Viera, 2017). The arm being measured has to be
held at the level of the heart on a level surface (Viera, 2017). In order to obtain correct blood
pressure readings, the blood pressure should be measured in a quiet environment where the medical
practitioner may listen to the brachial artery with a stethoscope and hear the Korotkoff noises
(Vischer and Burkard, 2017). As you progressively deflate the blood pressure cuff (two to three
mmHg per second), keep an ear out for the Korotkoff noises (Vischer and Burkard, 2017). Before
taking a person's blood pressure, they should empty their bladder because this might raise it by as
much as 15/10 mmHg (Viera, 2017).
To guarantee accuracy, several blood pressure measurements (at least two) should be taken
at intervals of 1-2 minutes (Vischer and Burkard, 2017). For a period of 12 to 24 hours, ambulatory
blood pressure monitoring is the most reliable way to confirm the diagnosis (Siu, 2015). Those
with extremely high blood pressure readings especially when there is compromised organ function
are an exception to this rule (Siu, 2015).
 Following a diagnosis of hypertension, medical professionals should work to determine the
underlying reason using risk factors and any other symptoms that may be present. Preadolescent
children are more likely to experience secondary hypertension, with renal illness being the main
reason in most cases. Obesity and a history of hypertension in the family are two of the many risk
factors for primary or essential hypertension, which is more prevalent in adults and adolescents
(Dukalska et al., 2006). Additionally, laboratory testing can be utilized to rule out the possibility
of secondary hypertension and assess if hypertension has harmed the kidneys, heart, or eyes. Since
diabetes and high cholesterol are additional risk factors for the development of heart disease and
may need to be treated, further testing for these disorders is typically conducted (Carretero and
Oparil, 2000).

2.1.4 CLASSIFICATION OF BLOOD PRESSURE

In order to define normal blood pressure, prehypertension, hypertension (stages I and II),
and isolated systolic hypertension (a condition that is frequently seen in the elderly), new
categorization guidelines are recommended. The average of sitting blood pressure measurements
that were accurately taken over two or more doctor visits is used to calculate these readings. When
a person's blood pressure is continuously at least 140 mmHg systolic or 90 mmHg diastolic in
those over 50, it is deemed to be hypertension. Patients requiring further care if they have renal
disease, Type 1 or Type 2 diabetes, or blood pressure more than 130/80 mmHg (Chobanian et al.,
2003).

TABLE 2.1: Classification of blood pressure

Systolic Pressure Diastolic Pressure

Classification
mmHg kPa (KN/m2) mmHg kPa (KN/m2)
Normal 90-119 12-15.9 60-79 8.0-10.5
Prehypertension 120-139 16.1-18.5 80-89 10.8-11.9
Stage 1 140-159 18.7-21.2 90-99 12.0-13.2
Stage 2 ≥160 ≥21.3 ≥100 ≥13.3
Isolated Systolic
≥140 ≥18.7 <90 <12.0
Hypertension
Source: American Hearts Association (2003) (Chobanian et al., 2003).
2.1.5 PREVENTION OF HYPERTENSION

Many persons who do not receive a hypertension diagnosis bear a large portion of the
illness burden associated with high blood pressure (Williams et al., 2004). Population efforts are
therefore necessary to lessen the effects of high blood pressure and the requirement for
antihypertensive drugs. It is advised to make lifestyle modifications to reduce blood pressure
before beginning medication. For the primary prevention of hypertension, the 2004 British
Hypertension Society recommendations (Williams et al., 2004) suggested lifestyle modifications
that were in accordance with the 2002 US National High Blood Pressure Education Program
guidelines (Whelton et al., 2002) and they include;

i. Maintain an adult's normal body weight, such as a body mass index of 20–25 kg/m2.
ii. Lower daily sodium consumption to less than 100 mmol (or less than 6 g of sodium chloride
or less than 2.4 g of sodium).
iii. Participate in brisk walking or other regular aerobic exercise for at least 30 minutes most
days of the week.
iv. Eat a diet high in fruits and vegetables, consuming five or more servings daily;
v. Restrict alcohol intake to no more than three units for males and two units for women per
day.
Managing stress or avoiding it altogether might help one regulate their blood pressure.
Several methods of relaxation that can aid in stress relief include;
i. Medication
ii. Yoga
iii. Warm bath
iv. Going on long walks (MacGill, 2015).
A single antihypertensive medicine may not reduce blood pressure as much as an effective
lifestyle change. Using two or more lifestyle changes in combination can provide even greater
benefits (Williams et al., 2004). There is strong evidence that cutting back on salt in the diet
decreases blood pressure, but it is unclear if this also lowers the risk of death and cardiovascular
disease (Mente et al., 2016). Both an estimated daily salt consumption of ≥6g and <3g is linked to
an increased risk of mortality or severe cardiovascular disease; however, the correlation between
excessive sodium intake and unfavorable outcomes is limited to those with hypertension (Mente
et al., 2016).
2.1.6 MANAGEMENT OF HYPERTENSION
One analysis from 2003 found that lowering blood pressure by 5 mmHg can lower the risk
of ischemic heart disease by 21%, stroke by 34%, dementia, heart failure, and cardiovascular
disease-related death by 25% (Law et al., 2003). The following measures can be employed in the
management of high blood pressure or hypertension;
i. Target Blood Pressure: Guidelines about the appropriate blood pressure target during
hypertension treatment have been developed by a number of expert groups. For the general
population, these groups advise setting a goal below the range of 140–160/90–100 mmHg
(Daskalopoulou et al., 2015). Similar goals are suggested by Cochrane studies for subgroups
including diabetics and those who have had cardiovascular disease in the past (Saiz,2022).
Furthermore, Cochrane studies have shown that the risks associated with aiming to reach
a blood pressure target that is lower than usual (at or below 140/90 mmHg) exceed the benefits for
older people with moderate to high cardiovascular risk (Arguedas et al., 2020). It's possible that
these conclusions don't apply to other groups (Arguedas et al., 2020). A somewhat higher goal of
150/90 mmHg is advised by several expert groups for people older than 60 to 80 years old (Qaseem
et al., 2017). For those over 60, the JNC-8 and American College of Physicians propose a goal
blood pressure of 150/90 mmHg (James et al., 2014). However, some specialists within both
organizations disagree with this approach (Wright Jr et al., 2014). A similar objective as for the
general population is advised by some expert organizations, while others have suggested
significantly lower targets for those with diabetes (Mancia et al., 2013) or chronic renal disease
with protein loss in the urine (ISo, 2012). The optimal target and whether it should vary for high-
risk patients remain disputed (Brunström and Carlberg, 2016), despite the fact that some specialists
suggest more drastic blood pressure reduction than recommended by some standards (Xie et al.,
2016).
In 2017, the American Heart Association published guidelines recommending medication
for those who have never had cardiovascular disease and have a 10-year risk of cardiovascular
disease of less than 10% if the systolic blood pressure is greater than 140 mmHg or the diastolic
blood pressure is greater than 90 mmHg (Whelton et al., 2018). It suggests taking medication if
the diastolic blood pressure is more than 80 mmHg or the systolic blood pressure is greater than
130 mmHg for persons who have had cardiovascular disease or who have a 10-year risk of
cardiovascular disease of more than 10% (Whelton et al., 2018).
ii. Lifestyle Modification: Modifying one's diet, increasing physical activity, and losing
weight are all part of the first line of treatment for hypertension. A Cochrane systematic review
revealed no evidence (due to lack of data) for impacts of weight reduction diets on death, long-
term complications, or adverse events in people with hypertension, despite the fact that all of these
have been advised in scientific recommendations (Go et al., 2014). Blood pressure and body
weight did really decline, according to the review (Semlitsch et al., 2021). Their potential efficacy
is comparable to, and occasionally greater than, that of a single drug (Mancia et al., 2013). Even
if the level of hypertension is low enough to not require medication right away, lifestyle
modifications should still be made in addition to medication.
Low-sodium diets (Huang et al., 2020), plant-based diets, the DASH diet (Dietary
Approaches to Stop Hypertension) (Sacks et al., 2001), which performed best among 11 other diets
in an umbrella review, and low-sodium diets have all been demonstrated to lower blood pressure
(Joshi et al., 2020). Although there is some evidence that drinking green tea can help decrease
blood pressure, not enough is known to suggest green tea as a therapy (Xu et al., 2020).
There may be an advantage to increasing dietary potassium in terms of reducing the risk of
hypertension (Stone et al., 2016). One of the deficiencies that Americans eat insufficient amounts
is potassium, according to the 2015 Dietary Guidelines Advisory Committee (DGAC) (DGAC,
2015). However, due to the danger of excessive potassium levels, patients using certain
antihypertensive drugs (such ACE-inhibitors or ARBs) shouldn't take potassium supplements or
potassium-enriched salts (Raebel, 2012).
Although there is no proof that stress-reduction methods like transcendental meditation or
biofeedback may prevent cardiovascular disease on their own, they can be used in conjunction
with other therapies to lower blood pressure (Nagele et al., 2014). Though further research is
needed, self-monitoring and appointment reminders may complement the use of other tactics to
enhance blood pressure control (Glynn et al., 2010). Activity programs that focus on isometric
resistance, aerobic activity, resistance training, and device-guided breathing have been
demonstrated to lowe r blood pressure (Brook et al., 2013).
iii. Medications: For the treatment of hypertension, a number of drug classes collectively
known as antihypertensive medications are used. Angiotensin converting enzyme inhibitors (ACE
inhibitors), calcium channel blockers, thiazide-diuretics, and angiotensin receptor blockers
(ARBs) are among the first-line treatments for hypertension (Wright et al., 2018). Although it is
not advised to take ACE inhibitors and ARBs together, these drugs can be used separately or in
combination. The latter option may help to reduce the counter-regulatory mechanisms that act to
return blood pressure readings to their pre-treatment levels (James et al., 2014). Most people need
more than one medicine to keep their blood pressure under control (Go et al., 2014).
In the past, it was believed that beta-blockers, like atenolol, had comparable advantages
when utilized as initial treatment for hypertension. Nonetheless, a Cochrane analysis comprising
thirteen trials concluded that beta-blockers' ability to prevent cardiovascular disease is not as strong
as that of other antihypertensive drugs (Wiysonge et al., 2017).
2.2 MENOPAUSE
The menstrual cycle permanently ends at the menopause, sometimes referred to as the
climacteric, signifying the cessation of reproduction (Moline and Clerke, 2023). Between the ages
of 45 and 55 is when it usually happens, though the precise time can change (Aninye et al., 2021).
Usually, menopause is a normal transition. Tobacco smokers may experience it early (Soares and
Warren, 2009). Other reasons could be bilateral ovarian excision surgery or certain kinds of
chemotherapy (Aggarwal et al., 2022). The physiological reason of menopause is a reduction in
the ovaries' ability to produce progesterone and estrogen (Moline and Clerke, 2023). Menopause
can be diagnosed by blood or urine hormone levels, however this is usually not necessary (Saad et
al., 2019). Menarche, or the beginning of a girl's menstrual cycle, is opposite of menopause
(Wood, 2017).
A woman's cycles usually become irregular in the years leading up to menopause (Care,
2017). This implies that the length of her periods might vary, as can the amount of flow (Care,
2017). Women frequently have hot flashes during this time; these can be accompanied by shaking,
nocturnal sweats, and skin reddening. Typically, they last between 30 and 10 minutes (Care, 2017).
Recurrences of hot flashes (Care, 2017) might last four to five years (Holloway, 2023). Mood
swings, difficulty sleeping, and vaginal dryness are possible additional symptoms (Care, 2017).
Women's symptoms differ in intensity (Holloway, 2023). The phrase "early menopause" refers to
menopause before the age of 45, and "premature ovarian insufficiency" refers to ovarian failure or
surgical removal of the ovaries before the age of 40 (Davis et al., 2015).
2.2.1 SIGNS AND SYMPTOMS OF MENOPAUSE
Menstrual cycles continue to be regular during the early stages of the menopause transition,
but the time between cycles starts to increase. Hormone levels start to change. Every cycle may
not result in ovulation (Oyadeyi, 2012). A year after the last menstrual cycle, a period of time is
known as the menopause (Oyadeyi, 2012). Women may come down with a variety of symptoms
both during and after the menopause (Care, 2017). However, bleeding patterns cannot be used to
identify the menopause, which is defined as the irreversible loss of ovarian function, in women
who approach the menopause transition without having regular menstrual cycles (due to previous
surgery, other medical issues, or continued hormonal contraception) (Davis and Baber, 2022).
Menstrual patterns may exhibit shorter cycles (by two to seven days) during the transition
to menopause, while lengthier periods are also possible (Oyadeyi, 2012). Uneven bleeding (Care,
2017) (lighter, heavier, spotting) may occur (Oyadeyi, 2012). Women who are approaching
menopause frequently experience dysfunctional uterine hemorrhage as a result of the hormonal
changes that coincide with this transition. Spotting or bleeding could be a normal endometrial
reaction, a benign sore (polyp or lesion), or it could just be connected to vaginal atrophy. The
endometrium, which is typically the primary cause of spotting or bleeding, can be assessed using
the criteria published by the European Menopause and Andropause Society (Dreisler et al., 2013).
Unplanned vaginal bleeding in postmenopausal women, however, should be taken seriously and
should be thoroughly investigated to rule out the possibility of malignant illnesses.
Although psychological symptoms are frequently described, they are not unique to
menopause and may result from other causes (Hogervorst et al., 2022) (Kilpi et al., 2020). They
consist of reduced interest in sexual activity, anxiety, impatience, poor memory, difficulty
concentrating, depressed mood, and mood swings (Oyadeyi, 2012) (Care, 2017). Cognitive
impairment associated with menopause should not be mistaken with moderate cognitive
impairment preceding dementia (Panay et al., 2020). There is evidence of slight average declines
in verbal memory, which could be brought on by the brain's reaction to a drop in estrogen levels
(Birkhaeuser and Genazzani, 2018) or possibly by the brain's decreased blood supply during hot
flashes (McPhee et al., 2010). But for the majority of women, symptoms usually go away after
menopause. Subjective accounts of memory and focus issues are linked to a number of variables,
including stress and sleep deprivation (Hogervorst et al., 2022) (Kilpi et al., 2020).
 Women who are exposed to endogenous estrogen during their reproductive years are
protected from cardiovascular disease for approximately ten years following the onset of
menopause. An increase in insulin resistance, dyslipidemia, endothelial dysfunction, and fat mass
(mostly visceral fat) are linked to the menopausal transition (Nappi et al., 2022). Women who
experience vasomotor symptoms during menopause and those who enter menopause early (before
45 years of age) (Stevenson et al., 2021) appear to have particularly unfavorable cardiometabolic
profiles (Thurston, 2018). By controlling risk factors such tobacco use, high blood pressure,
elevated blood cholesterol levels, and excess weight, these risks can be decreased (Souza and
Tezini, 2013).
The two years following the last menstrual cycle and the year preceding it have the highest
annual rates of bone mineral density decrease (Warming et al., 2002). Women who have gone
through menopause are therefore more susceptible to osteopenia, osteoporosis, and fractures.
2.2.2 CAUSES OF MENOPAUSE
Menopause can happen naturally or be induced. Medical procedures like radiotherapy,
chemotherapy, oophorectomy, tubal ligation problems, hysterectomy, unilateral or bilateral
salpingo-oophorectomy, or leuprorelin use can all lead to induced menopause (Thakur et al.,
2019).
i. Age: The menopause usually sets in between the ages of 47 and 54 (Thakur et al., 2019).
Several data points indicate that over 95% of women experience their last menstrual cycle between
the ages of 44 and 56 (median 49–50). The final bleeding occurs in 2% of women under 40, 5%
between 40 and 45, and the same percentage between 55 and 58 (Morabia et al., 1998). Over the
past year, the average age in the US is 51 years old, in Russia it is 50 years old, in Greece it is 49
years old, in Turkey it is 47 years old, in Egypt it is 47 years old, and in India it is 46 years old
(Ringa, 2000). The perimenopause, also known as the menopausal transition, typically lasts 3-5
years, however it can occasionally last up to 14 years (Care, 2017).
Rarely, a woman's ovaries may stop producing eggs at a fairly young age which can be
anywhere between puberty and age 40. This condition is also known as premature ovarian failure,
this condition affects 1–2% of women by the time they are 40 (Podfigurna-Stopa et al., 2016).
ii. Premature ovarian insufficiency: If the ovaries quit working before the age of forty, this
condition is known as premature ovarian insufficiency (POI) (Laissue, 2015). High blood levels
of luteinizing hormone (LH) and follicle stimulating hormone (FSH) on at least three occasions,
separated by at least four weeks, are used to diagnose or confirm it (Kalantaridou et al., 1998).
Because premature ovarian insufficiency may be auto immune, it can coexist with other
autoimmune conditions such diabetes mellitus and thyroid illness. Radiation therapy,
chemotherapy, and having the fragile X syndrome gene are among the other factors (Fenton, 2015).
Premature ovarian insufficiency is typically idiopathic, meaning that the reason is unclear in 50–
80% of instances (Kalantaridou et al., 1998) (Laissue, 2015).
iii. Surgical menopause: Bilateral oophorectomy (removal of the ovaries) is one surgical
method that can induce menopause. This procedure is frequently, but not always, combined with
uterine (hysterectomy) and fallopian tube removal (salpingo-oophorectomy) (Rahmouni et al.,
2012). "Surgical menopause" refers to the end of menstruation following ovarian excision. Ovarian
excision and other surgical procedures may completely end menstruation (Harlow et al., 2012).
Severe withdrawal symptoms, including hot flashes, may result from the abrupt and total decline
in hormone levels. Early menopausal symptoms could be more severe (Harlow et al., 2012).
2.2.3 DIAGNOSIS OF MENOPAUSE
The majority of women become aware of menopause symptoms and indicators without
receiving an official diagnosis from the doctor. The earliest symptoms are typically hot flashes and
a shift in menstruation cycle. Healthcare professionals can measure the levels of hormones
estradiol, follicle-stimulating hormones (FSH) and luteinizing hormone (LH) in the blood or urine.
These tests can be used to determine whether a woman is menopausal (MedlinePlus, 2011).
The body produces more FSH and LH hormones during menopause as a way to make up
for the ovaries’ decreased sensitivity to these hormones. Hormones such as estradiol also start to
decline around menopause.
2.2.4 MECHANISM OF MENOPAUSE
Generally speaking, postmenopause and the menopausal transition are natural changes
rather than symptoms of an illness. The aging and natural depletion of the limited supply of oocytes
(ovarian reserve) is the primary cause of this change. This process is known to happen sooner
following a variety of gynecologic surgeries, including uterine artery embolization, endometrial
ablation, and hysterectomy (with or without ovariectomy). It is occasionally expedited by other
disorders. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels rise when the
ovarian reserve is depleted because fewer oocytes and follicles are able to respond to these
hormones and produce estrogen. The transition has a different degree of impact (Cohen et al.,
2006).
In younger women, the pituitary gland's production of luteinizing hormone (LH) and free
stromal hormone (FSH) regulates the ovaries' cyclical production of progesterone, testosterone,
and estradiol during a normal menstrual cycle. Estradiol levels and production patterns are mostly
unchanged during perimenopause (the menopausal transition) or may even rise in comparison to
young women, but cycles are often shorter or more irregular (Prior, 1998). It is assumed that the
frequently seen rise in estrogen is a reaction to high FSH levels, which are thought to be brought
on by a reduction in inhibin feedback (Burger, 1994). Similarly, it is thought that diminished
inhibin feedback following a hysterectomy may be a factor in early menopause and greater ovarian
stimulation (Nahas et al., 2003).
The ovaries' abrupt reduction in the synthesis of progesterone and estradiol causes
menopause. Following menopause, aromatase in adipose tissues continues to produce the majority
of the estrogen that is produced. Small amounts of estrogen are also produced in many other
tissues, including the ovaries, bone, blood vessels, and the brain, where it has local effects
(Simpson and Davis, 2001). The considerable reduction in circulating estradiol levels at
menopause influences various tissues including the brain and skin.

2.2.5 STAGES OF MENOPAUSE

Over a woman’s lifespan, her reproductive health changes significantly. Hormones
undergo significant changes at each stage of life, from the first menstrual period to the childbearing
years and beyond to menopause and beyond. In general, there are four primary phases of
menopause;
i. Pre-menopause: A woman in her prime reproductive years, experiencing her regular
monthly cycle, and lacking any discernible menopausal symptoms is said to be in the
premenopausal period of life. In theory, a woman can be considered pre-menopausal at any time
before perimenopause (MedlinePlus, 2011).
ii. Peri-menopause: Literally meaning "around the menopause," the word "perimenopause"
describes the menopausal transition years prior to the date of the last episode of flow (Prior, 1998).
The North American Menopause Society states that four to eight years may pass during this
transition (McNamara et al., 2015). It is defined by the Centre for Menstrual Cycle and Ovulation
Research as a six- to ten-year phase that concludes one year after the last menstrual cycle (Prior,
1998). Estrogen levels are typically 20–30% greater during the perimenopause than they are
during the pre-menopause, although they can fluctuate greatly (Prior, 1998). Many of the physical
changes that occur during perimenopause and menopause are caused by these oscillations,
particularly in the final 1-2 years of perimenopause (the period that precedes menopause)
(Chichester and Ciranni, 2011). Hot flashes, nocturnal sweats, insomnia, mood swings, dry or
atrophy vagina, incontinence, osteoporosis, and heart disease are a few of these alterations (Prior,
1998). Additionally, depression is linked to perimenopause and affects 45–68% of peri-
menopausal women, with those who have previously had depression being twice as likely to
experience it (Marshburn and Hurst, 2011). Fertility decreases at this time, but it is not thought to
reach zero until the menopause is formally declared. The official date is established retroactively,
after a period of 12 months has elapsed since menstrual blood last appears.
The menopausal transition usually starts at age forty to fifty (average age forty-five)
(Marshburn and Hurst, 2011). Woman may have perimenopause for up to eight years (McNamara
et al., 2015). Menopause and perimenopause frequently begin at around the same time for women,
though this is not always the case (Ahmed, 2017).
iii. Menopause: The natural, permanent cessation of menstruation brought on by an estrogen
deficit that is unrelated to a pathologic disease is known as menopause. The Greek terms men,
which means month, and pausis, which means stop, are the origin of the term menopause. When
a woman experiences amenorrhea for a full year, it indicates the end of her reproductive and
childbearing years (Karasu, 2021). For most women, this happens between the ages of 45 and 56.
In the US, the median age of natural menopause is 51 years old (Mangione et al., 2022).
iv. Post-menopause: If a woman has a uterus and is not pregnant or nursing, she is considered
"postmenopausal" if she has not had a menstrual flow for at least a year (Harlow et al., 2012). A
blood test that reveals an extremely high FSH level can be used to diagnose menopause or
postmenopause in women who doesn’t have a uterus. Postmenopause, then, is the period of a
woman's life that follows her last menstrual cycle or, more precisely, the time after her ovaries
stop producing eggs.
The irregularity of periods throughout this stage of life is the cause for the delay in
announcing postmenopause. Consequently, it takes a fair amount of time to be certain that the
cycling has stopped. A woman is deemed infertile at this time; nevertheless, before this point is
reached, her chances of getting pregnant are typically extremely low, if not completely
nonexistent.

Figure 2.1: Stages of menopause

2.3 IMMUNOLOGICAL RESPONSES
An organism's physiological reaction during inflammation that serves as defense against
exogenous factors is known as an immune response. These exogenous factors encompass an
extensive range of diverse poisons, viruses, bacteria both extracellular and intracellular, protozoa,
helminths, and fungus that, if left unchecked, could pose a significant threat to the host organism's
health (Sompayrac, 2022). There are further types of immunological response. For instance,
innocuous external stimuli (such pollen and food ingredients) can cause allergies; recognized
allergens include latex and metals. Graft-versus-host disease can be brought on by an organ or
tissue transplant (blood, for example). Pregnant women may exhibit Rh illness, a form of
immunological reactivity. Hypersensitivity is the term used to describe these unique immune
response types. Antitumor immunity is an additional distinct type of immune response.
The innate and adaptive immune responses are the two main branches of the immune
response that cooperate to defend the body against infections. Both branches work with cellular
and humoral elements. The body's initial response to an invader, which is the innate branch, is
recognized to be a swift and non-specific defense against any kind of infection. Physical barriers
like the skin and mucous membranes, immune cells like neutrophils, macrophages, and monocytes,
and soluble components like complement and cytokines are all parts of the innate immune response
(Rich, 2018). However, because the adaptive branch of the immune system targets certain
antigens, it takes longer for the necessary components to become active. The adaptive branch
includes cells like B, T, and dendritic cells as well as antibodies, also called immunoglobulins,
which interact directly with antigen and are crucial for mounting a powerful defense against an
invader (Sompayrac, 2022).
2.3.1 Innate immune response: An organism's first defense against foreign intruders is known
as the innate immune response. All multicellular animals possess some variant of an innate
reaction, which has been evolutionarily conserved across numerous species (Shots, 2001). Physical
barriers like skin and mucous membranes, different cell types like neutrophils, macrophages, and
monocytes, and soluble components like complement and cytokines make up the innate immune
system (Rich, 2018). The innate response, which functions swiftly to purge the body of infections,
is not unique to any one foreign invader, in contrast to the adaptive immune response. Pattern
recognition receptors (PRR) are used to identify and detect pathogens. These macrophage surface
features are called receptors, and they have the ability to attach to foreign invaders and start
immune cell signaling. The pathogen-associated molecular patterns (PAMPs), which are essential
structural elements of pathogens, are specifically identified by the PRRs. PAMPs include the
lipopolysaccharides (LPS) and peptidoglycan cell wall, which are both vital components of
bacteria and have evolved to be conserved across a wide range of bacterial species (Rich, 2018).
The PRRs on macrophages are able to identify and bind to particular PAMPs when a
foreign pathogen manages to get past the physical barriers and into an organism. When this binding
occurs, a signaling pathway is activated, allowing the transcription factor NF-κB to enter the
macrophage nucleus and start transcription, leading to the eventual production of several cytokines
such TNFα, IL-1, and IL-8 (Abraha, 2018). For neutrophils to enter the infected tissue from blood
vessels, these cytokines must be released. Like macrophages, neutrophils are able to phagocytize
and eliminate any infections or germs once they have entered the tissue.
Figure 2.2: The innate immune response to gram-negative bacteria invasion.
Three different routes make up the complement system, another component of the innate
immune system, and they are all triggered differently. When IgG or IgM binds to its target antigen
on the pathogen cell membrane or an antigen-bound antibody, the classical cascade is activated.
The alternative route can autoactivate as a result of the "tickover" of C3, and it is triggered by
foreign surfaces such as bacteria, fungi, viruses, and parasites. When mannose-binding lectin
(MBL), also known as ficolin or particular pattern recognition receptors, attaches itself to
pathogen-associated molecular patterns on the surface of invasive microorganisms such yeast,
bacteria, parasites, and viruses, the lectin pathway is activated (Sarma and Ward, 2011).
If one of the three paths fails or a foreign invader manages to get past one of them, the
other two pathways guarantee that complement will continue to function (defense in depth
principle) (Abraha, 2018). The overarching function of the complement system is to opsonize
pathogens and trigger a series of inflammatory responses that aid in the fight against infection,
even though the pathways are activated differently.
Figure 2.3: The complement system pathway

2.3.2 Adaptive immune response: The body's second line of defense is the adaptive immune
response. Because B and T cells have antigen receptors that are specific to only a few antigens
throughout their early developing stages, the cells that make up the adaptive immune system are
incredibly specialized. For the activation of B and T cells, this is crucial. Extremely dangerous
cells, B and T cells can start eradicating the host's own healthy cells if they are able to attack
without passing through a rigorous activation process (Bonilla and Oettgen, 2010).

When antigen-presenting cells (APCs) display foreign antigen on their cell surface through
MHC class II molecules, naïve helper T cells become activated. These APCs, which are uniquely
furnished with MHC class II and co-stimulatory ligands that are recognized by co-stimulatory
receptors on helper T cells, comprise dendritic cells, B cells, and macrophages. T cells would
become anergic and the adaptive immune response ineffective without the co-stimulatory
chemicals. Certain APCs can activate distinct T cell subgroups, and every T cell is uniquely suited
to combat every type of microbial infection. The circumstances surrounding the APC's initial
interaction with the antigen influence the kind of T cell that is activated and the kind of reaction
that is produced (Janeway et al., 2001).

Helper T cells have the ability to stimulate naïve B cells in the lymph node once they are
activated. B cell activation, however, requires two steps. Prior to the antigen being presented on
the B cell's MHC class II molecules, it must first bind to the B cell receptors, which are simply the
immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies unique to that particular B cell.
Following this, the B cell is activated by a T helper cell that recognizes the antigen attached to the
MHC and binds with its co-stimulatory molecule. Consequently, the B cell transforms into a
plasma cell and secretes antibodies that function as an opsonin to ward off invaders.

The adaptive branch's specificity results from the uniqueness of each B and T cell. As a
result, a varied community of cells is prepared to identify and combat a wide variety of intruders
(Bonilla and Oettgen, 2010). The trade-off is that because the cells of the adaptive immune system
are so particular and need to be activated before they can function, the reaction is substantially
slower than the body's innate response. The adaptive immune response is recognized for its
immunological memory in addition to its specificity. The immune system creates memory T and
B cells in reaction to an antigen, enabling a quicker, more powerful immune response should the
organism come into contact with it again (Bonilla and Oettgen, 2010).

Figure 2.4: Major histocompatibility complex (MHC) peptide presentation along with co-
stimulatory ligand/receptor binding
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