Describe the uterine events associated with menstruation.

The menstrual cycle of the human female is approximately 28 days long and is numbered from the first day of the menses. Menstruation is the process in which the lining of the uterus is shed once during each cycle, a process that in most women takes 4 to 5 days. under influence of increasing titers of plasma estrogen, the endometrium of uterus increases in thickness, reaching a maximal width of 3 to 5 mm just prior to ovulation. Stromal connective tissue cells proliferate and extracellular collagen deposits are increased. In response to luteal phase progesterone levels, uterine glands increase in complexity from simple tubular elements during follicular phase of cycle to thick, coiled structures with a glandular lumen containing abundant secretory material. Spiral arteries within the endometrium become thickened and engorged with blood, particularly in response to luteal levels of progesterone. If implantation of a zygote fail to occur, then by about 11 days following ovulation, lymphocytes begin to invade the endometrium, and by day 14, sloughing of the endometrium occurs due to loss of ovarian steroid hormone support. In the absence of a hormonal directive, the spinal arteries become constricted and the blood lost from these arteries along with stromal debris composes the bulk of menstrual flow.
The nature of cervical mucus is also characteristically altered during the menstrual cycle. During the follicular phase, the mucus is rather thin and watery. In response to periovulatory levels of progesterone, the mucus becomes thickened and is composed of innumerable tiny channels that apparently provides access for the sperm through the cervical.

Different responses of epinephrine in various tissues. Explain?

In skeletal muscle :

Epinephrine causes glycogen breakdown. In response to stress, there is a need to mobilize glucose- release it from storage so it can be broken down to provide energy. Therefore need to increase glycogen breakdown (and decrease glycogen synthesis) in muscle (and liver). PKA is activated in skeletal muscles, which phosphorylates phosphorylase kinase, glycogen phosphorylase, thus decreasing its activity of glycogen synthesis.

In smooth muscle of lung:

Epinephrine causes muscle relaxation. in response to stress, need to breathe more deeply. Therefore, smooth muscles around the tubes that carry air, (bronchioles) relax. In smooth muscle surrounding the bronchioles, PKA phosphorylates a protein (MLCK), which is an active kinase needed for muscle contraction. MLCK must bind Ca2+ (in the form of a calmodulin/ Ca2+ complex). If MLCK is phosphorylated, the Ca2+/calmodulin complex cannot bind to it, and contraction does not occur.

However, in peripheral circulation, smooth muscles around blood vessels (arterioles) contract, diverting blood from peripheral circulation to essential internal organs.

There are two basic types of epinephrine receptors- called alpha and beta adrenergic receptors. these two types of receptors activate different G proteins and generate different second messengers.

a) beta-receptors- G protein type(Gs)- cAMP response- PKA- relaxation

b) alpha-receptors- different G protein (Gp)- IP3 (second messenger)- binds to receptor on ER                  membrane-m opens Ca2+ channels in ER- Ca2+ release- contraction.

Why POMC is considered as a multifunctional precursors?

Proopiomelanocortin (POMC) is a large protein (31,000 Daltons), which is isolated from both the pars distalis and the pars intermedia of the pituitary gland. This protein, POMC, contains sequences of corticotropin (adrenal cortical stimulating hormone, ACTH) and beta-LPH (beta-Lipotropic hormone). The first 13 amino acids of ACTH are identical to those of alpha-MSH. In the pars distalis ACTH is released under certain physiological conditions to regulate adrenocortical function. In the pars intermedia, on the other hand, enzymes are present within the secretory granules and are responsible for the enzymatic cleavage of POMC to alpha-MSH. Following cleavage from the precursor protein, post-translational amidation and acetylation of the C terminus and N terminus, respectively, of the MSH molecule then occurs. Thus, the precursor protein, POMC, contains within its primary structure the sequences of five MCs: alpha-MSH, beta-MSH, gamma-MSH, ACTH and beta-LPH, as well as several opiate peptides. Hence, it is considered as the multifunctional precursors.

Some receptors cross talk with each other.

• Although for simplicity, we treated individual signaling pathways as separate sequences of events leading to separate metabolic consequences, there is in fact extensive cross talk among signaling systems.
• The regulatory circuitry that governs metabolism is richly interwoven and multilayered.
• We study the signaling pathway for insulin and epinephrine separately, but they do not operate independently.
• Insulin opposes the metabolic effects of epinephrine in most tissues, and activation of the insulin signaling pathway directly attenuates signaling through the beta-adrenergic signaling system.
• For example, the INSR kinase directly phosphorylate two Tyr residues in the cytoplasmic tail of a beta-adrenergic receptor, and PKB activated by insulin, phosphorylates two ser residues in the same region.
• Phosphorylation of these four residues triggers clathrin-aided internalization of the beta-adrenergic receptor, taking it out of service and lowering the cell's sensitivity to epinephrine.
• A second type of cross talk between these receptors occurs when phosphorylated- tyr residues on the beta-adrenergic receptor, phosphorylated by INSR, serve as nucleation points for SH2 domain- containing protein such as Grb2.
• Activation of the MAPK ERK by insulin is 5- to 10 fold greater in presence of beta-adrenergic receptor, presumably because of this cross talk.

Explain the anti-inflammatory and hyperglycemic actions of glucocorticoids.

Hyperglycemic action of glucocorticoids.

Glucocorticoids affect carbohydrates, lipid and protein metabolism. They increase synthesis of a number of key enzymes in gluconeogenesis pathway within hepatocytes. Although the actions of glucocorticoids on the liver are anabolic, the actions on skeletal muscle and adipose tissue are catabolic. Catabolic actions may result because glucose uptake of these tissues is inhibited by glucocorticoids. In the absence of a metabolic substrate for ATP production, proteolysis of muscle proteins and lipolysis of fat occurs. The free fatty acids (FFAs) and amino acids that are released from these tissues become available as substrate for gluconeogenesis within the liver.
The glucose produced is either stored as glycogen or released into the blood. Excessive secretion of glucocorticoid is antagonistic to the actions of insulin and predisposis the individual to diabetes mellitus as the actions of glucocorticoid elevate blood glucose levels. Glucocorticoid also reduce the affinity of certain cells for insulin, which further aggravate the diabetic hyperglycemia.

Anti-inflammatory actions of glucocorticoids.

At higher than physiological concentration, as in Cushing's disease, glucocorticoids inhibit inflammatory and allergic reactions. These actions may result from stabilization of lysosomal membranes that prevents the secretion of enzymes that normally occurs during inflammation. Glucocorticoid inhibit the infiltration of leukocytes into the affected tissue and also exert an immunosuppressive action through their lympholytic actions.

Glucocorticoids cause atrophy of the lymphatic system (lymph nodes, thymus gland, spleen) , which results in decreased levels of circulating lymphocytes. Ultimately, this lymphocytopenia results in failure of the body to provide antibodies during an injection. Although, glucocorticoid may be useful in combating the undesirable effects of local injections, excessive use of these agents may render the individual susceptible to severe systematic bacterial infection as many protective mechanisms are suppressed, but the underlying cause of the disease remains.

Interleukin-1 (IL-1), a member of a family of polypeptides produced by activated monocytes and other cells elicit a variety of physiological reactions observed during injection, inflammation and injury.

Stimulation of ACTH release may be one of these important non-immune responses that can be induced by monokine. Stimulation of ACTH release by IL-1-beta may contribute to a homeostatic regulation of the immune function. Increased hypothalamus--pituitary-adrenal activity results in an increased secretion of glucocorticoid that suppress immune responses and hence unfavorable overstimulation of the immune reaction, during injection.

Increased secretion of glucocorticoid would represent a way for the body's natural defense mechanism to control the undesirable symptoms such as arthritis, induced by increased production of IL-1-beta observed in Lyme disease.

Hence IL-1-beta play an important role as a carrier of messages from immune system to neuroendocrine system.

Goitre is seen in both hyper and hypothyroidism. Comment.

The term goiter refer to the abnormal enlargement of thyroid gland. It is important to know that presence of goiter does not mean that the gland is malfunctioning. One of the most common cause of goiter formation worldwide is iodine deficiency. The primary activity of thyroid gland is to concentrate iodine from blood to make thyroid hormone. The gland cannot make enough thyroid hormone if it does not have enough iodine i.e., with iodine deficiency the individual will become hypothyroid. Consequently, the pituitary gland in brain senses the thyroid hormone level is too low and sends signal to thyroid. This signal is called thyroid stimulating hormone. This hormone stimulates the thyroid to produce thyroid hormone and to grow in size. This abnormal growth in size produces goiter. Thus iodine deficiency is one cause of goiter development. Another common cause of goiter is Grave's disease. In this one immune system produces a protein called thyroid stimulating immunoglobulin (TSI). As with TSH, TSI stimulate the thyroid gland to enlarge produce a goiter. However, TSI also stimulates the thyroid to make too much thyroid hormone (causes hyperthyroidism). Since pituitary senses too much thyroid hormone, it stop secreting TSH. Inspite, thyroid gland continues to grow and make thyroid hormone. 

List the function of granulosa cells. What are the effect of LH surge on ovarian function ?

Granulosa cells or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (oocyte or egg) in ovary of mammals.
The major function of granulosa cell include the production of sex steroids as well as myriad growth factors thought to interact with the oocyte during the development. The sex steroids production begins with FSH from the anterior pituitary, stimulating granulosa cells to convert androgens (from thecal cells) to estradiol by aromatase during follicular phase of menstrual cycle.
LH (Luteinizing hormone) is a hormone produced by gonadotropic cells in anterior pituitary gland. In females an acute rise of LH surge trigger ovulation and development of corpus leuteum.
The increase in LH production only last for about 24 to 48 hours. This LH surge trigger ovulation thereby not releasing the egg from the follicle but also initiating the conversion of the residual follicle into a corpus luteum that in turn produce progesterone to prepare the endometrium for a possible implantation. LH is necessary to maintain luteal function for the second two weeks for menstrual cycle. If pregnancy occurs, LH levels will decrease and luteal function will instead be maintained by the action of hCG (Human chorionic gonadotropin) a hormone similar to LH but secreted by new placenta.