Here is a list of seven main hormones found in animals. They are: 1. Progestins 2. Antiprogestins 3. Luteolytics 4. Thyroid Hormones 5. Parathormone 6. Calcitonin 7. Insulin.
Contents
Hormone # 1. Progestins:
Progesterone is naturally secreted from corpus luteum. It is also secreted from Placental cells in some species like horse, sheep, dog and cat but not from those of rabbit, pigs and goats. Whether the placenta of cows secrete progesterone or not is doubtful.
The adrenal cortex and testes may also secrete progesterone in certain adverse conditions. A number of progesterones are available in the market. The synthetic ones are far cheaper than the natural ones. The terms ‘Progestin’ is used to denote all types of progesterone.
A. Pharmacological Actions of Progestins:
The pharmacological actions of progestin follow the prescribed course of its physiological functions, and has been exploited therapeutically.
The actions can be grouped as under:
I. Action on hypothalmico-hypophyseal axis:
High concentrations of progestin in circulation inhibits release of Gn-RH and p- Gn, and thus blocks ovulation resulting into no return of estrus in most species. Withdrawal of progestin from circulation abolishes this inhibitory influence on hypothalamico-hypophyseal axis causing luteolysis and subsequent ovulation.
II. Action upon ovary and reproductive tract:
(a) Progesterone being ovulatory hormone induces ovulation from matured graafian follicle(s) in cow, rat, rabbit etc. when administered in small doses.
(b) It is the primary pregnancy hormone and its deficiency may lead to abortion.
(c) It is a natural immuno-suppressant to the mother’s rejection mechanism against the foetus. The foetus contains antigen from father which may not be compatible with that of the mother. Hence the mother may reject the foetus. The immuno-suppressant activity of progesterone is very similar to that of glucocorticoids.
(d) It brings about differentiation of the endometrium- the estrogen primed endometrium undergoes further growth. The endometrial ducts ramify and become tortuous
(e) The endometrial glands develop, become active and secrete(s) a thick nutritious fluid called uterine milk.
(f) It makes uterus suitable for nidation and growth of the newly formed zygote.
(g) It increases the electrical potential difference across the myometrial membrane and thereby prevents its easy excitation, and thus reduces the spontaneous rhythmic myometrial contractile force.
(h) It changes the thin cervical and vaginal secretory fluid into thick and tenacious one that tend to occlude the cervix.
(i) It regulates the length and size of diestrum in general and in case of no fertilization indirectly regresses the corpus luteum.
(j) Progesterone causes further growth of the estrogen primed mammary gland. A definite lobuloalveolar system capable of secreting milk develops.
(k) High level of progesterone in circulation delays onset of parturition in certain species of animals (rabbit), but it does not seem true in cows.
(I) Progesterone can suppress estrogen induced fibromyomata in animals.
(m)Some of the synthetic progestins possess estrogenics, androgenic and/or anabolic actions.
III. Action on metabolism:
(a) Its mineralocorticoids like action on Na+ is disputed. Many authors attribute Na+ retaining capability to it while others say no, rather emphasise loss of Na+& CI–.
(b) It probably possesses some anabolic property. It is stated so because pregnancy lead to increase in appetite and better feed utilization.
B. Chemistry and Mode of Action:
Progestins are steroid in nature. Structure of Progesterone and some other progestins are presented in Fig 22.12. Progestins act through cytoplasmic receptors.
C. Fate of Progestins in the Body:
Estrogens and Progesterone both are weakly but extensively bound to plasma proteins for transport. Of the rest estrogen is weakly bound to Sex Steroids Binding Protein (SSBP) while progesterone is strongly bound to transcortin. Natural progesterone when fed orally undergoes fast degradation while passing through entero- hepatic circulation. It is conjugated by the liver and then eliminated through kidneys.
Synthetic progesterones are degraded slowly by the liver and thus continue in the system for longer period.
D. Clinical Use:
Progesterone has been used to induce ovulation in repeat breeders and to calm down nymphomanic cows. It has also been used to prevent embryonic deaths in cattle. For better dairy management it has been used for synchronization of estrus and induction of lactation. It is also recommended for use in bitches to suppress estrus but for shorter durations only.
Hormone # 2. Antiprogestins:
Drugs which inhibit the action of progesterone are termed as antiprogestins. Mifepristone a derivative of norethisterone possesses such activity and its administration inhibits uterine glandular secretory activity, accelerates degenerative and vascular changes leading to recycle.
The changes are very similar to progesterone withdrawal syndrome. But when administered in higher doses it blocks proliferative action of estrogen in the endometrium leading to its atrophy, and suggests of its progestin agonist activity. Thus it can be said that Mifepristone acts as progestin antagonist in presence of progesterone but acts as progestin agonist in absence of the latter.
Short term administration of mifepristone decreases the secretion of LH, but on long term administration the secretion of LH is increased. Administration of mifepristone during pregnancy/gestation disrupts placental function and may lead to abortion. Simultaneous administration of PGF2α enhances its abortive activity.
Mifepristone when administered orally is metabolised slowly and hence can be used for terminating pregnancy. The drug in appropriate doses and in combination with PGF2α can be used to terminate pregnancy and to dilate cervix.
Hormone # 3. Luteolytics:
After ovulation the ruptured follicles re-organise and develop into Corpus Luteum (CL). The CL contains lutin cells (Theca lutin + Grannulosa lutin). The lutin cells particularly Grannulosa cells secrete large amounts of progesterone and very little amount of estrogen.
Presence of Progesterone in circulation regulates length of diestrum in general and if fertilization occurs then further maintains the condition of endometrium for nidation and pregnancy to continue.
In case of no fertilization the CL regresses under indirect influence of its own secretory product progesterone. For spontaneous regression of the cycling CL presence of normal functioning uterus is the most important factor. It has been stated that high level of progesterone in circulation brings about luteolysis.
It does so in the following ways:
(i) Pogesterone exerts an inhibitory influence on release of p-Gn and there by lack of trophic effect on CL which leads to regression of the latter.
(ii) Under influence of progesterone the non-pregnant normal endometrial glands secrete a substance called Prostaglandin F2α which causes luteolysis.
(iii) In absence of the above two influences the CL may regress automatically because of aging. But this occurs of late.
In certain other conditions where the uterus is not functioning normally the CL may persist for longer periods creating a condition of no return to estrus. This demands treatment. The old practice is to infuse some local irritants in the uterus, to denude the persisting undesired endometrial layer so that it may grow fresh.
The newly grown endometrial layer then secretes PGF2α to cause luteolysis. Such therapy included intrauterine (I.U.) administration of saline or lugol’s iodine or some suitable antibiotics. But with availability of PGF2α the trend has changed.
Prostaglandins:
Prostaglandins (PGs) are derivatives of Prostanoic acid, a 20- carbon unsaturated fatty acid found in almost all tissues of mammals. They are rapidly metabolised and act close to the site of their formation. PGs are actually not hormones in true sense but are some times classified as local hormones and many times under autocoids. They are named by letters (A, T, F, and G, H) and script numbers (1, 2, 3 etc.)
In veterinary practice the PGF2α appears to be most important since it influences reproduction. The endometrial tissues under height of CL function secretes PGF2α which initiates luteolytic process. Luteolysis is an inherent mechanism and in normal cycling females need no exogenous support.
PGF2α induces lutoeolysis in the following two different ways:
(a) On secretion the PGF2α is absorbed into the uterine vein and is reabsorbed counter currently into the ovarian artery to produce its vasoconstriction. This lead to reduction in blood supply to the ovaries and consequently to the CL which then undergoes regression.
(b) Conversion of cholesterol into prgesterone occurs under influence of cAMP. PGF2α inhibits adenylate cyclase enzyme system and thereby reduction/stoppage in production of cAMP leading to fall in progesterone formation and degeneration/regression of CL.
In dairy cattle the exogenous PGF2α administered during proestrus phase fails to induce luteolysis. Similarly it fails to haesten the process of luteolysis once it has already set in. Hence PGF2α is an effective luteolytic agent in dairy cows only when the CL is matured and functional.
Therapeutic Indications and Doses:
PGF2α has been used in cows in conditions of endometritis, pyometra, perssistant CL, retained mummified foetus, for abortion of early gestation, induction of labour in late gestational phase and termination of prolonged gestation. In dairy cows, sheep, mare and certain other species of animals it has been used for synchronization of estrus, and along with other drugs in superovulation schedules.
Fixation of dose according to body weight, species and purpose is yet to be ascertained, however, a general dose schedule is given below.
Preparations and Doses:
Hormone # 4. Thyroid Hormones:
The gland located at the upper part of trachea and once known as laryngeal gland is now called Thyroid (Fig 22.13a). The cross section of thyroid gland is presented in Fig 22.13(b). It consists of two highly vascular lobes joined together by a thin isthmus. The secretion of the gland is popularly called Thyroxine, though it consists of four fractions out of which two (T3 & T4) are biologically active and functional.
Thyroxine does not seem essential for life however, it is necessary for normal growth and reproduction. The active element of Thyroxine is Iodine. The actual requirement of iodine in daily diet of different species is not clearly known, however, in-order to prevent goiter all animals need 1 µg/kg/ iodine daily, the gravid ones need 4 µg/kg daily. Dogs need higher amount of iodine in their daily diet and it comes to about 15 µg/kg daily.
A. Biosynthesis and Regulation of Secretion of Thyroxine:
Thyroxine is synthesised in the thyroidal follicular cells and is stored in the colloids as thyroglobulin (TG). Formation of thyroxine right from uptake of iodides to its storage as TG and release is regulated by TSH (Fig. 22.13c). Higher titre of thyroxine in circulation inhibits hypothalamic nuclei while its lower titer in circulation stimulates the same and thereby controls release of TRH.
The amount of TRH so released in circulation affects Ant. pituitary for release of corresponding higher or lower amounts of Thyroxine from Thyroid gland. Secretion of Thyroxine also varies according to environmental temperature. Lower environmental temperature stimulates cold receptors on the skin, which sends afferent impulses to higher centres and consequently to the hypothalamus.
The hypothalamus then secretes TRH and thereby increased secretion and release of T4 & T3 with the help of TSH. The steps involved in iodination of tyrosine has been shown in Fig. 22.13(d). As clear from Fig. 22.13(c), TG does not enter into circulation. MIT and DIT also do not enter into circulation.
The amount of T3 & T4 secreted daily in different species of domestic animals is not clearly known however their serum levels in some of the domestic animals have been studied by RIA techniques. T4 is highest in cattle (6.22 ± 2.03 µg/ml) and lowest in dogs (1.51 ± 0.38 µg/ml) while T3 is highest in goats (145.9 ± 29.32 µg/ml) and lowest in cat (64.7 ± 20.62 µg/ml).
On entry into circulation T4 and T3 quietly bound themselves to serum protein. The target tissues pick them up according to requirement. None of the two circulate freely. Study on the topic is not very clear, however, curious readers are advised to refer reference books and journals to add more to their knowledge.
In addition to the above two factors for regulation of Thyroid secretions there exists one another method of its secretory regulation which is popularly called ‘Thyroid auto-regulation’. It is also known as “Wolff chaikoff effect”.
It works without the help of negative feed back mechanism and depends upon iodide trapping devise. Any increase in the iodide content of blood tends to enter into the gland cells. This tendency is locally inhibited by the local iodide trapping mechanism.
B. Physiological Functions of Thyroxine:
The exact mechanism by way of which T4/T3 work is not very clear however, it is claimed to work through increase in number of mitochondria per unit body tissue. Permeability of the mitochondrial membrane is increased facilitating certain phosphorylation reactions.
Metabolism of glucose, fat, protein, vitamins, minerals etc. is increased leading to increased BMR which is clearly marked in Thyroxine administered hypo-thyroids patients. Thyroxine stimulates oxygen consumption and heat production in all tissues except the brain, gonads, lymph nodes, spleen, thymus and dermis.
T4/T3 is necessary for normal functioning of the nervous system (CNS). Deficiency leads to failure in normal functioning of CNS and the animal may show lethargy, dull and stupid activity. But in adult animals it is reversible on administration of Thyroxine.
The intrauterine deficiency effect of Thyroxine does not allow myelination of nerves and it can not be corrected by substitution therapy. Thyroxine stimulates growth in combination with growth hormone and other related factors. Deficiency of Thyroxine affects reproductive performance both in male and female animals, without affecting spermatogenesis and oogenesis. It is a potent galactopoitic agent in dairy animals.
C. Fate of Thyroxine:
Both T4 and T3 are well absorbed when fed orally to carnivores. Thyroprotein, an iodinated casein with T4 like action when fed to cattle has been reported to be absorbed well. The half life time of T4 has been reported to be about 10 days which seems to be on higher side.
T4 serves as a pre-hormone to T3 since the former undergoes de-iodination before it is actually accepted by the target cells. Iodine so released joins the extra-thyroidal pool of iodine for reutilization, and a very little amount is excreted via bile or urine, while the tyrosine enters into the general metabolic pool.
The overall effect of T4 and T3 is similar, however, T3 acts quickly in small doses than T4. Tissues have 4 times higher affinity for T3 than T4.
D. Defects of Thyroid Metabolism:
The usual defects of thyroid metabolism can be grouped into two sets-viz; Hypothyoridism and Hyperthyroidism. Continuously, low level of Thyroxine in circulation lead to hypothyroidism while a reverse condition produces hyperthyroidism.
(a) Hypothyroidism:
Under physiologic condition it means lesser activity of thyroid gland. This leads to decreased tissue oxidation, fall in BMR and body temperature, increased deposition of glycogen and fat in depots. Slow down of all phypiological processes leading to a condition of myxoedema in adult human and cretinism in growing ones.
The condition of hypothyroidism is rarely observed in domestic animals except in dogs. However, whenever it occurs the animals go inactive, sleepy and lack vigour. They seek warm place to hide. If the appetite is normal the animal may gain weight. The hairs particularly around the face become thick and brittle. There may be full or partial alopecia a condition which may be confused with aging.
In iodine deficient areas pregnant animals not getting appropriate amount of iodine through feed produce cretinous off springs or stillbirths. Animals raised on scientific line with feed supplements overcome such troubles.
(b) Hyperthyroidism:
Increased level of Thyroxine in circulation speed up oxidation in all tissues of the body except in those mentioned earlier. In general there is increase in energy consumption by each cell with increase in BMR and body temperature.
Simultaneously there is increased sweating and increased mobilization of glucose and fat from depots. It speeds up all body process-increased appetite, heart rate, respiration rate, blood pressure etc. with fall in body weight. There is muscular tremor and nervousness. The animal remains excitable and apprehensive.
Increased glycolysis does not lead to increase in blood sugar level because of its simultaneous increased utilization by the body tissues. However, increased fat mobilization may lead to appearance of ketone bodies in the urine.
Metabolic requirement of all metabolites is increased. There is increased blood level of calcium and phosphorus due to increased osteoclastic activity. Domestic animals very rarely show hyperthyroidism and or adverse reactions of thyroxine-Thyrotoxicosis.
E. Radioactive Iodine:
Radioactive iodine. (131I) is selectively picked up and concentrated by the thyroid gland cells. It emits α and β radiations. Gamma radiation is used for external counting of thyroid function tests, while beta radiations penetrate only 2-3 mm in the soft tissues.
Since 131I is selectively picked up by the Thyroid cells it provides a very good method for study of Iodine uptake rate and thereby Thyroid function. Trapping of 131I by thyroid cells is measured by an isotope-counting device which detects y-radiation of the isotope emitted by the thyroid gland.
By this method increased, decreased, or normal uptake of iodine (131I) can be assessed. Response of thyroid to externally administered TSH can also be assessed by this method.
This technique has been widely applied in human patients. Its application in veterinary medicine till now is almost negligible.
Since β-radiation of 131I is destructive selectively to the Thyroidal cells it can be used therapeutically to destroy thyroid cells, administered in higher doses, provided the condition demands which should be studied very carefully.
F. Goitrogens:
Agents which interfere with production of Thyroxine and thereby stimulate more secretion of TSH, and cause enlargement of Thyroid gland (Goitter) are called Goitrogens.
According to the type of interference they produce goitrogens have been grouped into two:
(i) Which competitively inhibit up take of iodine by the gland cells. Examples – Thiocyanates, Percholates, and Periodates.
(ii) Which check iodination of Tyrosine, (a) Amino benzene group of chemicals like sulphonyl urea, 5-venyl thio-oxazolidine and sulphonamides. (b) Thiocarbamides like Thiourea, Thiouracil and Propyl thiouracil, Methyl thiouracil etc. do so.
G. Anti-thyroidal Drugs:
Drugs which interfere with BMR either by altering synthesis, release or peripheral action of Thyroxine are grouped as Anti-thyroidal drugs. They are used in hyper- thyroidal state. Goitrogens form the major group in this class. Other than Goitrogens iodine has also been used for this purpose and is the oldest method known. Iodine works in both conditions of hypothyroidism and hyperthyroidism.
However, it is more useful in hypo thyroidal state and little useful in hyper thyroidal conditions. The hyper thyroidal condition initially responds to the treatment given for a short period but when continued for longer period the hyper thyroidal condition may return and even may become more serious.
The mechanism of action of iodine in hypo thyroidal state is very clear that it works as substitution therapy and provides iodine to the Thyroidal cells for synthesis of Thyroxine. In hyper- thyroidal state administration of iodine blocks release of preformed T4/T3 from the gland cells. This phenomenon is known is “Thyroid constipation”. But this does not work longer. Soon the Thyroids escape out and restart working vigorously making the condition more serious.
H. Preparations and Doses:
Hormone # 5. Parathormone:
Parathyroids are four in number located on the ventral aspect of the thyroid gland, two on each lobe. Its number and location indicates its importance, and in-fact it is important for life since it regulates the metabolism of calcium. Biologically active parathormone (PTH) is secreted by the chief cells of the glands. It consists of 84 amino acids.
On entry into circulation the hormone is cleaved into two fractions: C-terminal fraction and N-terminal fraction. The N-terminal fraction is biologically active. It gets destroyed in the GI tract hence can not be administered orally.
PTH is synthesised and released continuously in the system, however, its secretion is increased under condition of hypocalcaemia. Increased level of vit A in circulation probably favours uptake of calcium by the gland cells which then disfavours release of the hormone. This leads to fall in the level of PTH in circulation.
PTH activates adenyl-cyclase enzyme system in the target cells and releases cAMP which increases permeability of the cells for calcium. In bone it favours conversion of mesenchymal cells into osteoclasts and inhibits osteoblasts.
It thus favours synthesis of collagens. The level of calcium in blood increases due to – (i) osteoclastic activity (ii) increased absorption of calcium from the G.I. tract and (iii) resorption of calcium from kidney tubules. It activates vit D3 in the kidneys. The activated vit D3 probably favours absorption of calcium from the G.I. tract. Thus the total sum effect of PTH is to increase the level of calcium in blood.
A. Defects of Parathyroid Metabolism:
The dysfunctions of the Parathyroid glands can be grouped as Hyperparathyroidism and Hypoparathyroidism.
(i) Hyperparathyroidism:
In this condition there is increased level of PTH in circulation. Such situation can arise due to (i) some functional lesion in the glands (ii) renal failure to resorb Ca2+ (iii) low calcium and high phosphorus diet. Whatever may be the reason for hyper functioning of the parathyroid the ultimate effect is the same.
There is increased decalcification of the bone and formulation of immature fibrous tissues in its place leading to deformity/fracture/or pain in the bones. Decalcification may also lead to deposition of Ca2+ in the soft tissues and even in the kidneys.
Such conditions are rarely seen in domestic animals. However, secondary hyperparathyroidism due to imbalance of Ca2+ and phosphorus ratio in the daily diet can be seen in all species which can be corrected by providing calcium supplement in the daily diet of the animals. Primary hyperparathyroidism due to adenoma of the glands has been reported in dogs.
(ii) Hypoparathyroidism:
In this condition the PTH level in circulation remains low leading to progressive decrease in blood calcium level. Such condition may arise due to severe pathologic conditions of the parathyroids or damage of the glands in some way or other. Whatever may be the cause the ultimate effect is low level of calcium in circulation leading to increased neuromuscular irritability and titany.
The bones tend to become more dense and there is increased elimination of Ca2+ in urine. Low level of calcium which is observed in milk fever can not be corrected by PTH administration.
However, it can be corrected by immediate calcium supplementation and maintenance of the level by feeding high calcium diet. The occurrence of milk fever can be prevented by feeding high calcium and vit D in diet for 1-2 months before parturition. PTH administration in prevention or cure of Milk fever is of no use.
Hormone # 6. Calcitonin:
It is secreted by the ‘c’ cells of Thyroid gland. It is a polypetide made up of 32 amino acids. Its mol. wt. is 3700. The whole hormone is required to exert biologic activity. The hormone obtained from salmon is highly active in mammals. The half life time of the hormone is 4-12 minutes.
It is secreted continuously under normocalcaemic state but its rate of secretion is increased with hypercalcaemia. Calcitonin acts directly on the bones and favours deposition of calcium.
It also works on kidneys and disfavours activation of vit D3 which in turn disfavours resorption of Ca2+ from intestine. It also favours elimination of Ca2+ and Po4, in urine. Thus the total sum effect of the hormone is to lower the level of calcium in blood.
‘C’ cell tumors have frequently been reported in bulls leading to increased level of Calcitonin in circulation and consequent hypocalcaemic state. Such tumors are less observed in cows and very less in canines. Lower level of Calcitonin in circulation has not been reported in domestic animals and therefore, its therapeutic value is not developed.
Hormone # 7. Insulin:
The islet of Langerhans contains four main cell types:
(i) B-cells – secrete insulin
(ii) A-cells – secrete glucagon
(iii) D-cells – secrete somatostatin
(iv) PP-cells – secrete pancreatic polypeptide
It is secreted from the beta cells of the islets of Langerhans and derives its name from a Latin word “insula” which means island. It is a life saving agent and has been fully synthesised in laboratory. It regulates glucose metabolism in the system and in absence/deficiency of it the individual suffers from hyper-glycaemia.
Glucose is the principal source of energy in non-ruminant animals. In absence of this hormone glucose enters into the tissues but only at higher blood concentrations which may cross the renal threshold level. At this point glucose escapes into the urine and the condition is called glucosurea.
Effective insulin action permits the tissues to utilize glucose at much lower blood concentration which is characterised as tissue threshold to glucose; and it is about 80-100 mg%. Insulin permits easy entry of glucose in the tissues and thus keeps the tissue threshold at a lower point.