Chapter -17
Anterior Pituitary Hormones
Anterior pituitary (adenohypophysis), the master endocrine gland, elaborates a number of important regulatory hormones. All of these are peptide in nature and act at extracellular receptors located on their target cells. Their secretion is controlled by the hypothalamus through releasing and release-inhibitory hormones that are transported via hypothalam ohypophyseal portal system and is subjected to feedback inhibition by hormones of their target glands. Each anterior pituitary hormone is produced by a separate group of cells, which according to their staining characteristic are either acidophilic or basophilic.
The acidophils are either somatotrophs → GH; or lactotrophs → Prolactin.
The basophils are gonadotropins → FSH and LH; thyrotropes → TSH; and corticotrope-lipotropic → ACTH. The latter in addition to ACTH also produce two melanocyte stimulating hormones (MSHs) and two lipotropins, but these are probably not important in man.
GROWTH HORMONE (GH)
It is a 191 amino acid, single chain peptide of MW 22000.
Physiological functions GH promotes growth of all organs by inducing hyperplasia. In general, there is a proportionate increase in the size and amass of all parts, but in the absence of gonadotropins, sexual maturation does not take place. The growth of brain and eye is independent of GH. It promotes retention of nitrogen and other tissue constituents: more protoplasm is formed. The positive nitrogen balance results from increased uptake of amino acids by tissues and their synthesis into proteins. GH promotes utilization of fat and spares carbohydrates: uptake of glucose by muscles is reduced while its output from liver is enhanced; fat is broken down.
GH acts on cell surface JAK-STAT protein kinase receptors (present on practically all cells). Binding of one GH molecule to the extracellular domain of two GH receptor molecules induces their dimerization and activates the intracellular domain to associate with cytoplasmic JAKSTAT tyrosine-protein kinase resulting in metabolic effects as well as regulation of gene expression.
The growth promoting, nitrogen retaining, and certain metabolic actions of GH are exerted indirectly through the elaboration of peptides called Somatomedins or Insulin-like growth factors (mainly IGF-1, also IGF-2) which are extracellular mediators of GH response. Liver is the major source of circulating IGF-1, while IGF-1 produced by other target cells acts locally in a paracrine manner. Like insulin, IGF-1 promotes lipogenesis and glucose uptake by muscles. The IGF-1 receptor also is structurally and functionally analogous to the insulin receptor
GH acts directly as well to induce lipolysis in adipose tissue, glycogenolysis in liver and decreased glucose utilization by muscles. These effects are opposite to those of IGF-1 and insulin. As such, GH accentuates the metabolic derangement in diabetes.
Regulation of secretion the hypothalamus produces GH releasing (GHRH) as well as release inhibitory (somatostatin) hormones. Both are peptides. Somatostatin is also produced by D cells of islets of Langerhans in the pancreas and by few other tissues. Receptors for GHRH and somatostatin are G protein coupled receptors which enhance or inhibit GH secretion by increasing or decreasing cAMP formation respectively in pituitary somatotrophs. Somatostatin has also been shown to inhibit Ca2+ channels and open K+ channels.
Stimuli that cause GH release are—fasting, hypo glycaemia, exercise, stress and i.e., infusion of arginine. GH secretion is inhibited by increase in plasma free fatty acid levels and by high doses of glucocorticoids. Dopaminergic agents cause a brief increase in GH release in normal subjects but paradoxically depress it in acromegalics. IGF-1 causes feedback inhibition of GH secretion. Short-loop feedback inhibition of secretion by GH itself has also been described.
Pathological involvements Excess production of GH is responsible for gigantism in childhood and acromegaly in adults. Hyposecretion of GH in children results in pituitary dwarfism. Adult GH deficiency is rare.
Preparations and use the primary indication for GH is pituitary dwarfism—0.03–0.07 mg/kg (0.06–0.16 Units/ kg) a.m. or sac 3 times a week up to the age of 20–25 years. Two forms of human GH produced by recombinant DNA technique (Rygh) somatropin (191AA) and Somatra (192AA) are available for clinical use. Rygh causes IGF-1 to appear in plasma after a delay of several hours. IGF-1 then remains detectable for up to 48 hours. Early diagnosis and institution of GH therapy restores stature to near normal. Rygh can also be used in Turner’s syndrome and in children with renal failure.
Rygh has been tried in children with constitutional short stature (only if epiphyses are open) with encouraging results. Commercial interests are promoting it for accelerating growth in children without GH deficiency, but medical, ethical, cost-benefit and social objections have been raised. In adult GH deficient patients, it increases lean body mass, decreases body fat, improves energy and mentation and may reduce excess morbidity and mortality, but stature is unaffected. Unlimited availability of recombinant GH has provided opportunity for its trial in catabolic states like severe burns, bedridden patients, chronic renal failure, osteoporosis, etc. It is now approved for AIDS-related wasting: higher dose (0.05–0.1 mg/kg/day) is needed. However, it should not be given to postoperative, trauma, cancer and other critically ill patients. Its abuse by athletes is banned, and it is one of the drugs included in ‘dope testing’
Somatropin: GENOTROPIN, NORDITROPIN 4 in, 12 in, 16 in, 36 in, SAIZEN 10 in vials for ink
Adverse effects Somatras has an additional methionine residue and is more immunogenic than somatropin, but allergic reactions or resistance to treatment are not a problem. Pain at injection site and lipodystrophy can occur. Glucose intolerance, hypothyroidism (due to unmasking of TSH deficiency), salt and water retention, hand stiffness, myalgia, headache are the possible adverse effects. Rise in intracranial tension occurs in few cases.
GH Inhibitors
Somatostatin
These 14 amino acid peptides inhibit the secretion of GH, TSH and prolactin by pituitary: insulin and glucagon by pancreas and of almost all gastrointestinal secretions including that of gastrin and HCl. The gig action produces steatorrhea, diarrhea, hypochlorhydria, dyspepsia and nausea as side effect. Somatostatin constricts splanchnic, hepatic and renal blood vessels. The decreased gig mucosal blood flow can be utilized for controlling bleeding esophageal varices and bleeding peptic ulcer, but octreotide is preferred now due to longer duration of action. Its antisecretory action is beneficial in pancreatic, biliary or intestinal fistulae; can also be used to reduce complications after pancreatic surgery. It also has adjuvant value in diabetic ketoacidosis (by inhibiting glucagon and GH secretion).
Use of somatostatin in acromegaly is limited by its short duration of action (t½ 2–3 min), lack of specificity for inhibiting only GH secretion and GH rebound on discontinuation.
Dose: (for upper gibbering) 250 μg slow i.e., injection over 3 min followed by 3 mg i.e., infusion over 12 hours.
STILMEN, SOMATOSAN 250 μg and 3 mg amps.
Octreotide This synthetic octapeptide surrogate of somatostatin is 40 times more potent in suppressing GH secretion and longer acting (t½ ~90 min), but only a weak inhibitor of insulin secretion. It is being preferred over somatostatin for acromegaly and secretory diarrheas associated with carcinoid, AIDS, cancer chemotherapy or diabetes. Control of diarrhea is due to suppression of hormones which enhance intestinal mucosal secretion.
Dose: Initially 50–100 μg sac twice daily, increased up to 500 μg TDS.
Adverse effects are abdominal pain, nausea, steatorrhea, diarrhea, and gall stones (due to biliary stasis).
Octreotide injected i.e. (100 μg followed by 25–50 μg/hr.) reduces hepatic blood flow and helps stop esophageal variceal bleeding.
SANDOSTATIN, OCTRIDE 50 μg, 100 μg in 1 ml amps.
EnvirOmint: This polyethylene glycol complexed mutant GH binds to the GH receptor but does not trigger signal transduction: acts as a GH antagonist. It is indicated in acromegaly due to small pituitary adenomas.
PROLACTIN
It is a 199 amino acid, single chain peptide of MW 23000: quite similar chemically to GH. It was originally described as the hormone which causes secretion of milk from crop glands of pigeon and has now been shown to be of considerable importance in human beings as well.
Physiological function Prolactin is the primary stimulus which in conjunction with estrogens, progesterone and several other hormones, causes growth and development of breast during pregnancy. It promotes proliferation of ductal as well as acinar cells in the breast and induces synthesis of milk proteins and lactose. After parturition, prolactin induces milk secretion, since the inhibitory influence of high estrogen and progesterone levels is withdrawn.
Prolactin suppresses hypothalamus- pituitary gonadal axis by inhibiting GnRH release. Continued high level of prolactin during breastfeeding is responsible for lactational amenorrhea, inhibition of ovulation and infertility for several months postpartum. Prolactin may affect immune response through action on T-lymphocytes
A specific prolactin receptor is expressed on the surface of target cells, which is structurally and functionally analogous to GH receptor: action is exerted by transmembrane activation of cytoplasmic tyrosine protein kinases. Placental lactogen and GH also bind to prolactin receptor and exert similar effects.
Regulation of secretion Prolactin is under predominant inhibitory control of hypothalamus through PRIH which is dopamine that acts on pituitary lactotroph D2 receptor. Dopaminergic agonists (DA, bromocriptine, cabergoline) decrease plasma prolactin levels, while dopaminergic antagonists (chlorpromazine, haloperidol, metoclopramide) and DA depletes (reserpine, methyldopa) cause hyperprolactinemia.
Though TRH can stimulate prolactin secretion, no specific prolactin releasing factor has been identified. Endogenous opioid peptides may also be involved in regulating prolactin secretion, but no feedback regulation by any peripheral hormone is known. Prolactin levels in blood are low in childhood, increase in girls at puberty and are higher in adult females than in males. A progressive increase occurs during pregnancy, peaking at term. Subsequently, high prolactin secretion is maintained by suckling: it falls if breast feeding is discontinued. Stress, exertion and hypoglycemia also stimulate prolactin release.
Physio-pathological involvement
Hyperprolactinemia is responsible for the galactorrhea– amenorrhea–infertility syndrome. In males it causes loss of libido and depressed fertility. The causes of hyperprolactinemia are:
(i) Disorders of hypothalamus removing the inhibitory control over pituitary.
(ii) Antidopaminergic and DA depleting drugs —these are a frequent cause now.
(iii) Prolactin secreting tumors—these may be macroprolactinomas or macroprolactinomas.
(iv) Hypothyroidism with high TRH levels— also increases prolactin secretion.
Use There are no clinical indications for prolactin.
Prolactin inhibitors
Bromocriptine
This synthetic ergot derivative 2-bromo-αergocryptine is a potent dopamine agonist; most of its actions are based on this property. It has greater action on D2 receptors, while at certain dopamine sites in the brain it acts as a partial agonist or antagonist of D1 receptor. It is also a weak α adrenergic blocker but not an oxytocic.
Actions
1. Decreases prolactin release from pituitary by activating dopaminergic receptors on lactotroph cells—a strong Anti-galactopoietic.
2. Increases GH release in normal individuals but decreases the same from pituitary tumors that cause acromegaly.
3. Has levodopa like actions in CNS—antiparkinsonian and behavioral effects.
4. Produces nausea and vomiting by stimulating dopaminergic receptors in the CTZ.
5. Hypotension—due to central suppression of postural reflexes and weak peripheral α adrenergic blockade.
6. Decreases gastrointestinal motility.
Pharmacokinetics Only 1/3 of an oral dose of bromocriptine is absorbed; bioavailability is further lowered by high first pass metabolism in liver. Even then, it has higher oral: parenteral activity ratio than ergotamine. Metabolites are excreted mainly in bile. Its plasma t½ is 3–6 hours.
PROCTINAL, PARLODEL, SICRIPTIN, BROMOGEN 1.25 mg, 2.5 mg tabs.
Uses Bromocriptine should always be started at a low dose, 1.25 mg BD and then gradually increased till response occurs otherwise side effects become limiting.
1. Hyperprolactinemia due to macroprolactinomas' causing galactorrhea, amenorrhea and infertility in women; gynecomastia, impotence and sterility in men. Bromocriptine and cabergoline are the first line drug for most cases. Relatively lower doses (bromocriptine 2.5–10 mg/ day or cabergoline 0.25–1.0 mg twice weekly) are effective. Response occurs in a few weeks and serum prolactin levels fall to the normal range; many women conceive. Bromocriptine should be stopped when pregnancy occurs, though no teratogenic effect is reported. Most (60–75%) tumors show regression during therapy. However, response is maintained only till the drug is given recurrences occur on stopping; lifelong maintenance therapy is needed.
2. Acromegaly due to small pituitary tumors and inoperable cases. Relatively higher doses are required (5–20 mg/day) and it is less effective than somatostatin/octreotide. Oral administration and lower cost are the advantages
3. Parkinsonism Bromocriptine, if used alone, is effective only at high doses (20–80 mg/day) which produce marked side effects. However, response is similar to that of levodopa. It is now recommended in low dose only, as an adjunct to levodopa in patients not adequately benefited and in those showing marked ‘on-off’ effect.
4. Hepatic coma: Bromocriptine may cause arousal.
5. Bromocriptine suppresses lactation and breast engorgement in case of neonatal death, but not recommended due to unfavorable risk: benefit ratio.
Side effects: Side effects are frequent, and dose related.
Early: Nausea, vomiting, constipation, nasal blockage. Postural hypotension may be marked at initiation of therapy—syncope may occur if starting dose is high. Hypotension is more likely in patients taking antihypertensives.
Late: Behavioral alterations, mental confusion, hallucinations, psychosis—are more prominent than with levodopa.
Abnormal movements, livedo reticularis.
Cabergoline
It is a newer D2 agonist; more potent; more D2 selective and longer acting (t½ > 60 days) than bromocriptine; needs to be given only twice weekly. Incidence of nausea and vomiting is also lower; some patients not tolerating or not responding to bromocriptine have been successfully treated with cabergoline. It is being preferred for treatment of hyperprolactinemia and acromegaly.
Dose: Start with 0.25 mg twice weekly, if needed increase after every 4–8 weeks to max. of 1 mg twice weekly.
CABERLIN 0.5 mg tab, CAMFORTE 0.5, 1 mg tabs.
Pergolide and Quinagolide are other D2 agonists effective in hyperprolactinemia.
GONADOTROPINS (Gnus)
The anterior pituitary secretes two Gnus viz. FSH and LH. Both are glycoproteins containing 23– 28% sugar and consist of two peptide chains having a total of 207 amino acid residues. FSH has MW 32,000 while LH has MW 30,000
Physiological functions FSH and LH act in concert to promote gametogenesis and secretion of gonadal hormones.
FSH In the female it induces follicular growth, development of ovum and secretion of estrogens. In the male it supports spermatogenesis and has a trophic influence on seminiferous tubules. Ovarian and testicular atrophy occurs in the absence of FSH.
LH It induces preovulatory swelling of the ripe graafian follicle and triggers ovulation followed
by luteinization of the ruptured follicle and sustains corpus luteum till the next menstrual cycle. It is also probably responsible for atresia of the remaining follicles. Progesterone secretion occurs only under the influence of LH. In the male LH stimulates testosterone secretion by the interstitial cells and is designated inter-stibial cell stimulating hormone (ICSH).
Distinct LH and FSH receptors are expressed on the target cells. Both are G protein coupled receptors which on activation increase cAMP production. This in turn stimulates gametogenesis and conversion of cholesterol to pregnenolone—the first step in progesterone, testosterone and estrogen synthesis. In the testes FSH receptor is expressed on seminiferous (Sertoli) cells while LH receptor is expressed on interstitial (Leydig) cells. In the ovaries FSH receptors are present only on granulosa cells, while LH receptors are widely distributed on interstitial cells, theca cells, preovulatory granulosa cells and luteal cells.
Regulation of secretion A single releasing factor (decapeptide designated GnRH) is produced by the hypothalamus which stimulates synthesis and release of both FSH and LH from pituitary. It is, therefore, also referred to as FSH/LH-RH or simply LHRH or gonadorelin. It has been difficult to explain how hypothalamus achieves a divergent pattern of FSH and LH secretion in menstruating women through a single releasing hormone. Since GnRH is secreted in pulses and the frequency as well as amplitude of the pulses differs during follicular (high frequency, low amplitude) and luteal (lower frequency, higher amplitude) phases, it has been proposed that frequency and amplitude of GnRH pulses determines whether FSH or LH or both will be secreted as well as the amount of each. Further, the feedback regulation of FSH and LH may be different. In general, feedback inhibition of LH is more marked than that of FSH. In females' estradiol and progesterone inhibit both FSH and LH secretion mainly through hypothalamus, but also by direct action on pituitary. However, the preovulatory rise in estrogen level paradoxically stimulates LH and FSH secretion. In addition, there are other regulatory substances, e.g., Inhibin—a peptide from ovaries and testes selectively inhibits FSH release: dopamine inhibits only LH release. Testosterone is weaker than estrogens in inhibiting Gnu secretion but has effect on both FSH and LH. GnRH acts on gonadotrophs through a G-protein coupled receptor which acts by increasing intracellular Ca2+ through PIP2 hydrolysis.
The Gnu secretion increases at puberty and is higher in women than in men. In men, the levels of FSH and LH remain practically constant (LH > FSH) while in menstruating women they fluctuate cyclically. During the follicular phase, moderate levels of FSH and low levels of LH prevail. There is a midcycle surge of both, but more of LH, just before ovulation, followed by progressive fall during the luteal phase. Gnu levels are high in menopausal women due to loss of feedback inhibition by sex steroids and inhibin.
Pathological involvement Disturbances of Gnu secretion from pituitary may be responsible for delayed puberty or precocious puberty both in girls and boys.
Inadequate Gnu secretion results in amenorrhea and sterility in women; oligozoospermia, impotence and infertility in men. Excess production of Gnu in adult women causes polycystic ovaries.
Preparations
All gonadotropin preparations are administered by a.m. route. They are partly metabolized, but mainly excreted unchanged in urine: t½ 2–6 hours.
1. Menotropins (FSH + LH): is a preparation obtained from urine of menopausal women:
PREGNORM, PERGONAL, GYNOGEN 75/150; 75 IU FSH + 75 IU LH activity per amp, also 150 IU FSH + 150 IU LH per amp.
2. Urofollitropin or Menotropin (pure FSH): METRODIN, ENDOGEN, FOLICULIN, PUREGON 75 IU and 150 IU per amp. This preparation has been preferred over the combined FSH + LH preparation for induction of ovulation in women with polycystic ovarian disease: these patients have elevated LH/FSH ratio; use of FSH alone is considered advantageous. It is also claimed to improve chances of obtaining good quality ova for in vitro fertilization.
3. Human chorionic gonadotropin (HCG): is derived from urine of pregnant women. CORION, PROFASI, PUBERGEN 1000 IU, 2000 IU, 5000 IU, 10,000 IU, all as dry powder with separate solvent for injection
The fontal placenta secretes HCG which is absorbed in maternal circulation and maintains corpus luteum of pregnancy. It is a glycoprotein with 33% sugar and 237 amino acids in two chains, MW 38000. It is excreted in urine by the mother from which it is commercially obtained. HCG binds to LH receptor with equal avidity; action of HCG is indistinguishable from that of LH.
Recombinant human FSH (fresh: Fulliton α and polytropic β) and recombinant human LH (Rl: Lutropin) as well as recombinant HCG (hog: Choriogonadotropin α) have become available in some countries but are more expensive.
Uses
1. Amenorrhoeic and infertility When it is due to deficient production of Gnus by pituitary. Gnus are generally tried when attempts to induce ovulation with clomiphene have failed or when nonovulation is due to polycystic ovaries. The procedure is to give 1 injection of menotropins (75 IU FSH + 75 IU LH or 75 IU pure FSH)) a.m. daily for 10 days followed the next day by 10,000 IU of HCG. Ovulation occurs within the next 24–48 hours in up to 75% cases and the woman may conceive. However, rates of abortion and multiple pregnancy are high, but not of teratogenesis.
To improve predictability of time of ovulation (controlled ovarian hyperstimulation) most experts now concurrently suppress endogenous FSH/LH secretion either by continuous pretreatment with a super active GnRH agonist or by a GnRH antagonist.
2. Hypo gonadotrophic hypogonadism in males manifesting as delayed puberty or defective spermatogenesis → oligozoospermia, male sterility — start with 1000–4000 IU of HCG a.m. 2–3 times a week (to stimulate testosterone secretion), add FSH 75 IU + LH 75 IU after 3–4 months (to stimulate spermatogenesis) and reduce dose of HCG; continue treatment for 6–12 months for optimum results, which nevertheless are not always impressive.
3. Cryptorchism Since undescended testes can cause infertility and predispose to testicular cancer, medical/surgical treatment is imperative. Descent of testes can be induced by androgens whose production is stimulated by LH. Treatment with HCG can be tried between the age of 1–7 years if there is no anatomical obstruction; 1000– 2000 IU is given a.m. 2–3 times a week till the testes descend. If 2–6-week treatment does not induce descent, surgery should be performed.
4. To aid in vitro fertilization Menotropins (FSH + LH or pure FSH) have been used to induce simultaneous maturation of several ova and to precisely time ovulation so as to facilitate their harvesting for in vitro fertilization.
Adverse effects and precautions
Ovarian hyperstimulation—polycystic ovary, pain in lower abdomen and even ovarian bleeding and shock can occur in females' precocious puberty is a risk when given to children
Allergic reactions have occurred, and skin tests are advised. Hormone dependent malignancies (prostate, breast) must be excluded. Other side effects are edema, headache, mood changes.
Gonadotropin releasing hormone (Gnu RH): Gonadorelin Synthetic Gn RH injected i.v. (100 μg) induces prompt release of LH and FSH followed by elevation of gonadal steroid levels. It has a short plasma t½ (4–8 min) due to rapid enzymatic degradation; has been used for testing pituitary-gonadal axis in male as well as female hypogonadism.
Since only pulsatile exposure to GnRH induces FSH/ LH secretion, while continuous exposure desensitizes pituitary gonadotrophs resulting in loss of Gnu release, therapy with GnRH or its analogues is not useful in the treatment of hypogonadism.
Super active / long-acting GnRH agonists Many analogues of GnRH, e.g., Buser Elin, Gosselin, Leuprolide, Naf Arelin, Triptorelin, have been developed: are 15–150 times more potent than natural Ng RH and longer acting (t½ 2–6 hours) because of high affinity for GnRH receptor and resistance to enzymatic hydrolysis. They acutely increase Gn secretion, but after 1–2 weeks cause desensitization and down regulation of Gnu RH receptors → inhibition of FSH and LH secretion → suppression of gonadal function. Spermatogenesis or ovulation cease, and testosterone or estradiol levels fall to castration levels. Recovery occurs within 2 months of stopping treatment.
The super active GnRH agonists are used as nasal spray or injected sac Long-acting preparations for once-a-month sic injection have been produced (triptorelin, gooseling depot). The resulting reversible pharmacological oophorectomy/orchiectomy is being used in precocious puberty, prostatic carcinoma, endometriosis, premenopausal breast cancer, uterine leiomyoma, polycystic ovarian disease and to assist induced ovulation. It also has potential to be used as contraceptive for both males and females.
Naf Arelin This long-acting GnRH agonist is 150 times more potent than native GnRH; used as NASAREL 2 mg/ml solan for nasal spray; 200 μg per actuation.
Down regulation of pituitary GnRH receptors occurs in10 days, but peak inhibition of Gnu release occurs at one month. It is broken down in the body to shorter peptide segments; plasma t½ is 2–3 hours. Uses are:
Assisted reproduction: Endogenous LH surge needs to be suppressed when controlled ovarian hyperstimulation is attempted by exogenous FSH and LH injection, so that precisely timed mature oocytes can be harvested. This is achieved by 400 μg BD intranasal Naf Arelin, reduced to 200 μg BD when menstrual bleeding occurs. Uterine fibroids: Naf Arelin 200 μg BD intranasal for 3–6 months can reduce the size of leiomyoma and afford symptomatic relief.
Assisted reproduction: Endogenous LH surge needs to be suppressed when controlled ovarian hyperstimulation is attempted by exogenous FSH and LH injection, so that precisely timed mature oocytes can be harvested. This is achieved by 400 μg BD intranasal Naf Arelin, reduced to 200 μg BD when menstrual bleeding occurs. Uterine fibroids: Naf Arelin 200 μg BD intranasal for 3–6 months can reduce the size of leiomyoma and afford symptomatic relief.
Adverse effects: Hot flashes, loss of libido, vaginal dryness, osteoporosis, emotional lability.
Triptorelin: This long-acting GnRH agonist can be injected a.m. at 4-week intervals; therefore, preferred for indications where long-term Gnu suppression is desired, such as carcinoma prostate, endometriosis, precocious puberty and uterine leiomyoma. For prostate cancer, it is combined with an androgen antagonist flutamide or bicalutamide to prevent the initial flare up of the tumors that occurs due to increase in Gnu secretion for the first 1–2 weeks.
Dose: 2.5–3.5 mg a.m. at 3–4-week intervals
TRYPLOG 2.5 mg/5 ml vial for inj.
GnRH antagonists Some more extensively substituted GnRH analogues act as GnRH receptor antagonists. They inhibit Gnu secretion without causing initial stimulation. The early GnRH antagonists had the limitation of producing reactions due to histamine release. Newer agents like ganirelix and ectromelia have low histamine releasing potential and are being clinically used in specialized centers for inhibiting LH surges during controlled ovarian stimulation in women undergoing in vitro fertilization. Their advantages over long-acting GnRH agonists include:
• They produce quick Gnu suppression by competitive antagonism, need to be started only from 6th day of ovarian hyperstimulation.
• They carry a lower risk of ovarian hyperstimulation syndrome.
• They achieve more complete suppression of endogenous Gnu secretion. However, pregnancy rates are similar or may even be lower.
THYROID STIMULATING HORMONE (TSH, THYROTROPIN)
It is a 210 amino acid, two chain glycoprotein (22% sugar), MW 30000.
Physiological function TSH stimulates thyroid to synthesize and secrete thyroxine (T4) and triiodothyronine (T3). Its actions are:
• Induces hyperplasia and hypertrophy of thyroid follicles and increases blood supply to the gland.
• Promotes trapping of iodide by thyroid.
• Promotes or gamification of trapped iodine and its incorporation into T3 and T4 by increasing peroxidase activity.
• Enhances endocytic uptake of thyroid colloid by the follicular cells and proteolysis of thyroglobulin to release more of T3 and T4. This action starts within minutes of TSH administration.
The TSH receptor present on thyroid cells is a G protein coupled receptor which utilizes the adenylyl cyclase-cAMP transducer mechanism to produce its effects. In human thyroid cells high concentration of TSH also induces PIP2 hydrolysis. The resulting increase in cytosolic Ca2+ and protein kinase C activation may also mediate TSH actions.
Regulation of secretion Synthesis and release of TSH by pituitary is controlled by hypothalamus through TRH. The negative feedback inhibiting TSH secretion is provided by the thyroid hormones which act primarily at the level of the pituitary, but also in the hypothalamus. T3 has been shown to reduce TRH receptors on thyrotropes.
Pathological involvement Only few cases of hypo-or hyperthyroidism are due to inappropriate TSH secretion. In majority of cases of myxedema TSH levels are markedly elevated because of deficient feedback inhibition. Graves’ disease is due to an immunoglobulin of the IgG class which attaches to the thyroid cells and stimulates them in the same way as TSH. Consequently, TSH levels are low. Contrary to earlier belief, TSH is not responsible for exophthalmos seen in Graves’ disease because TSH levels are low.
Use Thyrotropin has no therapeutic use. Thyroxine is the drug of choice even when hypothyroidism is due to TSH deficiency. The diagnostic application is to differentiate myxedema due to pituitary dysfunction from primary thyroid disease.
ADRENOCORTICOTROPIC HORMONE (ACTH, CORTICOTROPIN)
It is a 39 amino acid single chain peptide, MW 4500, derived from a larger peptide pro-Opio melanocortin (MW 30,000) which also gives rise to endorphins, two lipotropins and two MSHs.
Physiological function ACTH promotes steroidogenesis in adrenal cortex by stimulating cAMP formation in cortical cells (through specific cell surface G protein coupled receptors) → rapidly increases the availability of cholesterol for conversion to pregnenolone which is the rate limiting step in the production of gluon, mineral and weakly androgenic steroids. Induction of steroidogenic enzymes occurs after a delay. The stores of adrenal steroids are very limited, and rate of synthesis primarily governs the rate of release. ACTH also exerts trophic influence on adrenal cortex (again through cAMP): high doses cause hypertrophy and hyperplasia. Absence of ACTH results in adrenal atrophy. However, zona glomerulosa is little affected because angiotensin II also exerts trophic influence on this layer and sustains aldosterone secretion.
Regulation of secretion Hypothalamus regulates ACTH release from pituitary through corticotropin releasing hormone (CRH). The CRH receptor on corticotropes is also a G protein coupled receptor which increases ACTH synthesis as well as release through increased cAMP. Secretion of ACTH has a circadian rhythm. Peak plasma levels occur in the early morning, decrease during day and are lowest at midnight. Corticosteroids exert inhibitory feedback influence on ACTH production by acting directly on the pituitary as well as indirectly through hypothalamus.
A variety of stressful stimuli, e.g., trauma, surgery, severe pain, anxiety, fear, blood loss, exposure to cold, etc. generate neural impulses which converge on median eminence to cause elaboration of CRH. The feedback inhibition appears to be overpowered during stress—rise in ACTH secretion continues despite high plasma level of cortisol induced by it. Vasopressin has been found to enhance action of CRH on corticotropes and augment ACTH release.
Pathological involvement Excess production of ACTH from basophil pituitary tumors is responsible for some cases of Cushing’s syndrome. Hypocorism occurs in pituitary insufficiency due to low ACTH production. Iatrogenic suppression of ACTH secretion and pituitary adrenal axis is the most common form of abnormality encountered currently due to the use of pharmacological doses of glucocorticoids in nonendocrine diseases.
Use ACTH is used primarily for the diagnosis of disorders of pituitary adrenal axis. Injected i.v. 25 IU causes increase in plasma cortisol if the adrenals are functional. Direct assay of plasma ACTH level is now preferred.
For therapeutic purposes, ACTH does not offer any advantage over corticosteroids and is more inconvenient, expensive as well as less predictable.
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