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Changes in Levels of Sex Hormones and N-Terminal Pro–B-Type Natriuretic Peptide as Biomarker for Cardiovascular Diseases
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Considerable differences exist in the prevalence and manifestation of atherosclerotic cardiovascular disease (CVD) and heart failure (HF) between men and women. Premenopausal women have a lower risk of CVD and HF compared with men; however, this risk increases after menopause. Sex hormones, particularly androgens, are associated with CVD risk factors and events and have been postulated to mediate the observed sex differences in CVD.
B-type natriuretic peptides (BNPs) are secreted from cardiomyocytes in response to myocardial wall stress. BNP plays an important role in cardiovascular remodelling and volume homeostasis. It exerts numerous cardioprotective effects by promoting vasodilation, natriuresis, and ventricular relaxation and by antagonizing fibrosis and the effects of the renin-angiotensin-aldosterone system. Although the physiological role of BNP is cardioprotective, pathologically elevated N-terminal pro–BNP (NT-proBNP) levels are used clinically to indicate left ventricular hypertrophy, dysfunction, and myocardial ischemia. Higher NT-proBNP levels among individuals free of clinical CVD are associated with an increased risk of incident CVD, HF, and cardiovascular mortality.
BNP and NT-proBNP levels are higher in women than men in the general population. Several studies have proposed the use of sex- and age-specific reference ranges for BNP and NT-proBNP levels, in which reference limits are higher for women and older individuals. The etiology behind this sex difference has not been fully elucidated, but prior studies have demonstrated an association between sex hormones and NT-proBNP levels. Recent studies measuring endogenous sex hormones have suggested that androgens may play a larger role in BNP regulation by inhibiting its production.
Data were collected from a large, multiethnic community-based cohort of individuals free of CVD and HF at baseline to analyze both the cross-sectional and longitudinal associations between sex hormones [total testosterone (T), bioavailable T, freeT, dehydroepiandrosterone (DHEA), SHBG, and estradiol] and NT-proBNP, separately for women and men. It was found that a more androgenic pattern of sex hormones was independently associated with lower NT-proBNP levels in cross-sectional analyses in men and postmenopausal women.
This association may help explain sex differences in the distribution of NT-proBNP and may contribute to the NP deficiency in men relative to women. In longitudinal analyses, a more androgenic pattern of sex hormones was associated with a greater increase in NT-proBNP levels in both sexes, with a more robust association among women. This relationship may reflect a mechanism for the increased risk of CVD and HF seen in women after menopause.
Additional research is needed to further explore whether longitudinal changes in NT-proBNP levels seen in our study are correlated with longitudinal changes in sex hormones. The impact of menopause on changes in NT-proBNP levels over time should also be explored. Furthermore, future studies should aim to determine whether sex hormones directly play a role in biological pathways of BNP synthesis and clearance in a causal fashion. Lastly, the dual role of NTproBNP as both
a cardioprotective hormone and
a biomarker of CVD and HF, as well as
the role of sex hormones in delineating these processes,
should be further explored. This would provide a step toward improved clinical CVD risk stratification and prognostication based on
A major class of lipids, steroids, have a ring structure of three cyclohexanes and one
cyclopentane in a fused ring system as shown below. There are a variety of functional
groups that may be attached. The main feature, as in all lipids, is the large number of
carbon-hydrogens which make steroids non-polar.
Steroids include such well known compounds as cholesterol, sex hormones, birth
control pills, cortisone, and anabolic steroids.
The best known and most abundant steroid in the body is cholesterol. Cholesterol is
formed in brain tissue, nerve tissue, and the blood stream. It is the major compound
found in gallstones and bile salts. Cholesterol also contributes to the formation of
deposits on the inner walls of blood vessels. This topic was covered in the previous
discussion of the lipids series, and extensively in cardiovascular topics.
Cholesterol is synthesized by the liver from carbohydrates and proteins as well as fat.
Therefore, the elimination of cholesterol rich foods from the diet does not necessarily
lower blood cholesterol levels. Some studies have found that if certain unsaturated fats
and oils are substituted for saturated fats, the blood cholesterol level decreases.
The research is incomplete on this problem.
Cholesterol exists as an ester with fatty acids.What is the functional group at carbon 3
which is used to make an ester?
OH is alcohol
What is the feature on carbon 17?
Branched long hydrocarbon chain
The primary sex hormones, testosterone and estrogen, are responsible for the
development of secondary sex characteristics. Two female sex hormones,
progesterone and estrogen or estradiol control the ovulation cycle. Notice
that the male and female hormones have only slight differences in structures,
but yet have very different physiological effects.
Testosterone promotes the normal development of male genital organs and
is synthesized from cholesterol in the testes. It also promotes secondary male
sexual characteristics such as deep voice, facial and body hair.
Estrogen, along with progesterone regulates changes occurring in the uterus
and ovaries known as the menstrual cycle. Estrogen is synthesized from testosterone by making the first ring aromatic which results in the loss of a
methyl group and formation of an alcohol group.
List three functional groups in progesterone?
C#3 & #17 are ketones; C#4&5 are alkenes;
What is difference between progesterone and testosterone?
testosterone has C#17 alcohol vs ketone on progesterone
What is difference between testosterone and estrogen?
Estrogen has C#3 alcohol, + aromatic first ring;
no methyl group on C#17
Adrenocorticoid Hormones
The adrenocorticoid hormones are products of the adrenal glands.
The most important mineralcorticoid is aldosterone, which regulates the
reabsorption of sodium and chloride ions in the kidney tubules and increases
the loss of potassium ions.Aldosterone is secreted when blood sodium ion
levels are too low to cause the kidney to retain sodium ions. If sodium
levels are elevated, aldosterone is not secreted, so that some sodium
will be lost in the urine. Aldosterone also controls swelling in the tissues.
Cortisol, the most important glucocortinoid, has the function of increasing
glucose and glycogen concentrations in the body. These reactions are
completed in the liver by taking fatty acids from lipid storage cells and
amino acids from body proteins to make glucose and glycogen.
In addition, cortisol is elevated in the circulation with cytokine mediated
(IL1, IL1, TNFα) inflammatory reaction, called the systemic inflammatory
response syndrome. Its ketone derivative, cortisone, has the ability
to relieve inflammatory effects. Cortisone or similar synthetic derivatives
such as prednisolone are used to treat inflammatory diseases, rheumatoid
arthritis, and bronchial asthma. There are many side effects with the use
of cortisone drugs, such as bone resorption, so there use must be
monitored carefully. Cortisol is increased pathologically with the growth
of a pituitary gland tumor that secretes adrenocorticotropic hormone
(ACTH), called Addison’s Disease, which is also associated with
hirsuit features.
What is the only difference between cortisol and aldosterone?
Aldosterone has C#13 aldehyde instead of methyl group
Prostaglandins, are like hormones in that they act as chemical messengers,
but do not move to other sites, but work right within the cells where
they are synthesized. (PARACRINE)
Prostaglandins are unsaturated carboxylic acids, consisting of of a 20 carbon
skeleton that also contains a five member ring. They are biochemically
synthesized from the fatty acid, arachidonic acid.
The unique shape of the arachidonic acid caused by a series of cis double
bonds helps to put it into position to make the five member ring.
Prostaglandins are unsaturated carboxylic acids, consisting of a
20 carbon skeleton that also contains
a five member ring and
are based upon the fatty acid, arachidonic acid.
There are a variety of structures one, two, or three double bonds. On the
five member ring there may also be double bonds, a ketone, or alcohol groups.
In PGE2, list all of the functional groups.
one acid; two alkenes; two alcohols; one ketone
What is difference the C=C double bonds?
the upper is cis; the lower is trans.
There are a variety of physiological effects including:
Activation of the inflammatory response, production of pain, and fever.
When tissues are damaged, white blood cells flood to the site to
try to minimize tissue destruction. Prostaglandins are produced
as a result.
Blood clots form when a blood vessel is damaged. A type of
prostaglandin called thromboxane stimulates constriction and
clotting of platelets. Conversely, PGI2, is produced to have the
opposite effect on the walls of blood vessels where clots
should not be forming.
Certain prostaglandins are involved with the induction of labor
and other reproductive processes. PGE2 causes uterine
contractions and has been used to induce labor.
Prostaglandins are involved in several other organs such as
the gastrointestinal tract (inhibit acid synthesis and increase
secretion of protective mucus), increase blood flow in kidneys,
and leukotriens promote constriction of bronchi associated
with asthma.
When you see that prostaglandins induce inflammation, pain, and fever,
what comes to mind but aspirin. Aspirin blocks an enzyme called
cyclooxygenase, COX-1 and COX-2, which is involved with the ring
closure and addition of oxygen to arachidonic acid converting to
prostaglandins.
The acetyl group on aspirin is hydrolzed and then bonded to the
alcohol group of serine as an ester. This has the effect of blocking
the channel in the enzyme and arachidonic can not enter the active
site of the enzyme.
By inhibiting or blocking this enzyme, the synthesis of prostaglandins
is blocked, which in turn relives some of the effects of pain and fever.
Sphingolipids are a second type of lipid found in cell membranes, particularly
nerve cells and brain tissues. They do not contain glycerol, but retain the
two alcohols with the middle position occupied by an amine.
As shown in the graphic, sphingosine has three parts, a three carbon
chain with two alcohols and amine attached and a long hydrocarbon chain.
In sphingomyelin, the base sphingosine has several other groups attached
as shown in the graphic on the left. A fatty acid is attached to the amine
through amide bond. Phosphate is attached through a phosphate ester bond,
and again through a phosphate ester bond to choline.
The human brain and spinal cord is made up of gray and white regions.
The white region is made of nerve axons wrapped in a white lipid coating,
the myelin sheath, which provides insulation to allow rapid conduction of
electrical signals. Multiple sclerosis caused by a gradual degradation of
the myelin sheath.
Sphingomyleins are located throughout the body in nerve cell membranes.
They make up about 25 % of the lipids in the myelin sheath that surrounds
and insulates cells of the central nervous system.
Niemann-Pick disease is caused by a deficiency of an enzyme that breaks
down excessive sphingomyelin, which then builds up on the liver, spleen,
brain, and bone marrow. An effected child usually dies within several years.
Glycolipids are complex lipids that contain carbohydrates. Cerebrosides are an
example which contain the sphingosine backbone attached to a fatty acid and
a carbohydrate. The carbohydrates are most often glucose or galactose. Those
that contain several carbohydrates are called gangliosides. The example on the
left is shown with glucose. Glucocerebroside has the specific function to be in
the cell membranes of macrophages, (cells that protect the body by destroying
foreign microorganisms. Galactocerebroside is found almost exclusively in the
membranes of brain cells.
There are several genetic diseases resulting from the absence of specific enzymes
which breakdown the glycolipids. Tay-Sachs, which mainly effects Jewish children,
results in a build up of gangliosides and result in death in several years. Gaucher’s
disease results in the excessive build up of glucocerebroside resulting in severe
anemia and enlarged liver and spleen.
Calcium Dependent NOS Induction by Sex Hormones: Estrogen
Reporter and Curator: Sudipta Saha, Ph.D.
Nitric oxide (NO) synthases (NOSs) constitute a family of isozymes that catalyze the oxidation of L-arginine to NO and citrulline. First identified in the vascular endothelium, NO synthesis has subsequently been shown to play important roles in:
the regulation of vascular and gastrointestinal tone,
in cell-mediated cytotoxicity against bacteria and tumors, and
in a variety of central and peripheral nervous system activities.
NOSs can be divided into three functional classes based on their sensitivity to calcium.
The cytokine- or bacterial product-inducible isoenzyme iNOS binds calmodulin tightly at resting intracellular calcium concentrations.
The constitutive forms, isozymes eNOS (originally described in endothelial cells) and
nNOS (originally described in neuronal tissue), bind calmodulin in a reversible and calcium-dependent fashion.
The mechanisms by which their synthesis is controlled are unknown. The cDNA species encoding the rat, mouse, and human nNOS, the human and bovine eNOS, and iNOS from several species and cell types have been cloned and sequenced. The three human isozymes characterized to date are distinct, with their deduced protein sequences showing only 50-60%o amino acid identity. nNOS, which in rats and humans localizes to neurons in the central and peripheral nervous system and colocalizes with NADPHdiaphorase activity, has also been shown to be widely distributed in several non-neuronal tissues including human skeletal muscle.
It had been thought that both nNOS and eNOS were purely constitutive enzymes, although studies suggest eNOS may be induced by shear stress. Studies demonstrate that these NOSs can be induced in several tissues during pregnancy and in nonpregnant female and male animals by estradiol and that in skeletal muscle it is accompanied by an increase in NOS-specific mRNA.
Evidences emerging from various laboratories showed that there is an increase in the release of NO from the vasculature during pregnancy. Furthermore, treatment of pregnant animals at the end of gestation with tamoxifen reduced NOS activity in the cerebellum, an organ where tamoxifen acts as a pure estrogen-receptor antagonist. Thus, the increase in calcium-dependent NOS activity during pregnancy is mediated by estrogen. This conclusion is supported by the fact that treatment of nonpregnant females and male animals with estradiol also increased calcium-dependent NOS activity in all tissues studied.
Interestingly, testosterone treatment also increased cerebellar NOS activity without affecting other tissues. However, testosterone may increase brain NOS by directly binding estrogen receptors as has been reported. Furthermore, the cerebellum was the only tissue in the male to respond to a 5-day course of estradiol, suggesting that it may have a larger number and/or a greater availability of estrogen receptors than other tissues. In addition, the brain is rich in aromatase, which converts testosterone into estradiol. This, together with the observation that progesterone does not induce NOS, indicates that the induction of both nNOS and eNOS is specific for estrogen and not a characteristic of all sex steroids. These experiments do not exclude the possibility that the addition of progesterone might modify the estradiol effect.
The increases in NOS activity are the result of augmented enzyme synthesis (enzyme induction) since they are accompanied by increases in the specific mRNAs for both eNOS and nNOS. It is not, however, possible to tell whether the increases in mRNA are caused by an upregulation of mRNA synthesis (transcriptional induction) or decreased mRNA breakdown.
Although calcium-dependent NOS activity was increased by estradiol in tissues obtained from both female and male guinea pigs, a longer duration of treatment was necessary in the male. The most likely explanation for this observation is that the number or availability of estrogen receptors is initially too low in most tissues of the male and requires a period of estrogen priming. Although other factors may play a role, the duration of exposure may well explain the observation that the effect of pregnancy on NOS-specific mRNA is greater than estradiol alone.
The observation that estradiol induces calcium-dependent NOSs has several important implications:
An increase in release of NO from the endothelium would decrease vascular tone and contractility, events that are characteristic in pregnancy.
Heterogeneity among tissue endothelium regarding the effects of estrogen on basal NO release could explain the selective redistribution of maternal cardiac output to organs important for a successful pregnancy.
Consistent with this possibility is the observation that the effect of pregnancy on endothelium-derived NO is greatest in the uterine artery, followed by the mesenteric artery and then renal arteries.
An alternative hypothesis to explain the adaptation of smooth muscle to pregnancy is that it is caused by prostacyclin. Prostacyclin is increased during pregnancy and contributes to the observed reduced contractility of the ovine uterine artery to angiotensin II.
However, estradiol does not increase the synthesis of prostacyclin by the endothelium, nor does inhibition of prostacyclin synthesis prevent the effects of pregnancy on smooth muscle. In addition, both the incidence of esophageal reflux and the gastrointestinal transit time are increased during pregnancy. Although this phenomenon has previously been attributed to a direct effect of progesterone, NO is a powerful dilator of the gastrointestinal smooth muscle. If the increase in NOS activity observed in the esophagus applies to the bowel, enhanced NO might be the mechanism underlying both increased esophageal reflux and transit time.
The biological signifcance of an estradiol-dependent increase in the NOS in the central nervous system is of great interest and deserves further investigation. Furthermore, an estradiol-mediated increase in NOS in the vasculature could be the mechanism whereby premenopausal women are protected from coronary artery disease since increased NOS may slow the development of atherosclerosis and reduce the contractile response to acute thrombosis. Finally, the induction of calcium-dependent NOS enzymes by estradiol suggests that the present classification of this family of enzymes into constitutive and inducible types needs to be revised, since eNOS and nNOS enzymes at least are both constitutive and inducible.
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