Hypothalamic and Pituitary Hormones Flashcards
Mecasermin
Recombinant Growth Hormone
GH is used for replacement therapy in GH-deficient children, whether the deficiency is congenital or acquired. By convention, somatropin refers to the recombinant form of GH and is identical to the native form of human GH, while somatrem refers to a derivative of GH with an additional methionine at the amino terminus.
Although the greatest improvement in growth occurs in patients with GH deficiency, exogenous GH has some effect on height in children with short stature caused by factors other than GH deficiency.
Growth hormone affects many organ systems and also has a net anabolic effect. It has been tested in a number of conditions that are associated with a severe catabolic state and is approved for the treatment of wasting in patients with AIDS. Experimentally, GH has also been shown to increase intestinal growth and improve its function and it is approved for the treatment of patients with short bowel syndrome who are receiving specialized nutritional support.
A small number of children with growth failure have severe IGF-1 deficiency that is not responsive to exogenous GH. Mecasermin is recombinant human IGF-1 that can be used to treat this deficiency. The most important adverse effect observed with mecasermin is hypoglycemia.
Recombinant Growth Hormone Side Effects
In children, GH therapy is associated with remarkably few side effects. Rarely, generally within the first 8 weeks of therapy, patients develop intracranial hypertension, with papilledema, visual changes, headache, nausea, and/or vomiting. An increased incidence of type 2 diabetes mellitus has been reported (brought about due to GH induced hyperinsulinemia). Finally, too-rapid growth may be associated with slipped epiphyses or scoliosis. Patients with Turner syndrome have an increased risk of otitis media while taking GH.
In adults, side effects associated with the initiation of GH therapy include peripheral edema, carpal tunnel syndrome, arthralgia, and myalgia. In addition, GH treatment increases the activity of cytochrome P450 isoforms. There has been no increased incidence of malignancy among patients receiving GH therapy, but GH treatment is contraindicated in a patient with a known active malignancy.
Ocreotide
Somatostatin Analogs
Somatostatin inhibits the release of GH, TSH, glucagon, insulin and gastrin. Somatostatin has limited therapeutic usefulness because of its short duration of action and multiple effects in many secretory systems. A series of longer-acting analogs have been developed and revolutionized the medical treatment of acromegaly. Currently, the most widely used analog is octreotide. GI side effects including diarrhea, nausea and abdominal pain occur in up to 50% of patients treated with octreotide. In most patients, these symptoms diminish over time and do not require cessation of therapy. Approximately 25 % of patients develop gallstones, presumably due to decreased gallbladder contraction and GI transit time. Cardiac effects including bradycardia and conduction disturbances have also been reported.
Other clinical uses of octreotide include the acute control of bleeding from esophageal varices and in the treatment of secretory diarrhea.
Carbegoline and Bromocriptine
Dopamine Agonists
Although dopamine-receptor agonists normally stimulate GH secretion, they paradoxically decrease GH secretion in some patients with acromegaly. The best responses have been seen in patients whose tumors secrete both GH and prolactin. Bromocriptine and cabergoline are dopamine agonists (not analogs so can be given orally!) with a high affinity for dopamine D2 receptors. They can also be used to successfully treat hyperprolactinemia.
Frequent side effects of bromocriptine include nausea and vomiting, headache, and postural hypotension. Less-frequent side effects include nasal congestion, digital vasospasm, and CNS effects such as psychosis, hallucinations, nightmares or insomnia. Cabergoline is an ergot derivative with a longer half-life, higher affinity and greater selectivity for the D2 receptor than bromocriptine. Compared to bromocriptine, cabergoline has a much lower tendency to induce nausea, although it still may cause hypotension and dizziness.
Pegvisomant
GH Receptor Antagonists
Pegvisomant is a GH antagonist that is approved for the treatment of acromegaly. Pegvisomant binds to the GH receptor but does not activate JAK-STAT signaling or stimulate IGF-1 secretion.
Gonadotropin-releasing hormone
Luteinizing hormone (LH), follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) are collectively referred to as the gonadotropic hormones because of their actions on the gonads. Pituitary gonadotropin production is stimulated by GnRH and is further regulated by feedback effects of the gonadal hormones. The intermittent release of GnRH is crucial for the proper synthesis and release of the gonadotropins; the continuous release leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes. This down-regulation forms the basis for the clinical use of long-acting GnRH analogs to suppress gonadotropin secretion.
Leuprolide
GnRH analogs
Nafarelin
GnRH analogs
Goserelin
GnRH analogs
Gonadorelin
A number of clinically useful GnRH analogs have been synthesized. These include synthetic native GnRH (gonadorelin) and GnRH analogs (leuprolide, nafarelin, goserelin) which exhibit enhanced potency and a prolonged duration of action compared to GnRH.
The pharmacological castration induced by long-acting GnRH analogs is useful in disorders that respond to reductions in gonadal steroids (eg, in controlled ovarian hyperstimulation, endometriosis, uterine leiomyomata, prostate cancer, gondotropin-dependent precocious puberty, advanced breast and ovarian cancer, polycystic ovary disease etc.)
The long-acting agonists generally are well tolerated, and side effects are those that would be predicted to occur when gonadal steroidogenesis is inhibited eg, hot flashes, sweats, headaches, decreased bone density etc. Their use is contraindicated in both pregnant and breast-feeding women. The main drawback of these long-acting agonists is that gonadotroph suppression does not occur immediately; instead, there is a transient (several days) increase (‘flare’) in sex hormone levels, followed by a lasting suppression of hormone synthesis and secretion (this can be prevented with the use of GnRH antagonists).
Gonadorelin, which has a short half-life, can be administered in a pulsatile fashion to stimulate patterned gondaotropin release. Clinical uses include the treatment of both female and male (hypothalamic hypogonadotropic hypogonadism) infertility and in the diagnosis of LH responsiveness.
Ganirelix
GnRH Receptor Antagonists
Cetrorelix
GnRH Receptor Antagonists
The GnRH competitive receptor antagonists, ganirelix and cetrorelix, inhibit the secretion of FSH and LH in a dose-dependent manner. They are approved for preventing the LH surge during controlled ovarian hyperstimulation. They also suppress surges in LH in the early to mid-follicular phase of the menstrual cycle, resulting in improved rates of implantation and pregnancy. Both are well tolerated with the most common adverse effects being nausea and headache.
GnRH antagonists also have applications for palliation of metastatic prostate cancer. In this situation, a direct GnRH antagonist has the advantage of avoiding the initial surge in testosterone caused by treatment with GnRH agonists.
Gonadotropins
In women, the principal function of FSH and LH is to direct ovarian follicle development and ovarian steroidogenesis. Estrogen and progesterone production is primarily under the control of LH, whereas during pregnancy human chorionic gonadotropin (hCG) takes over. In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for testosterone synthesis.
Gonadotropins are purified from human urine or prepared using recombinant DNA technology. Human chorionic gonadotropin (hCG) mimics the action of LH, and is obtained from the urine of pregnant women. Urine from postmenopausal women is the source of menotropins, which contain roughly equal amounts of FSH and LH.
Urofollitropin is a highly purified FSH preparation, whilst two recombinant forms of FSH are also available; follitropin alfa and follitropin beta.
Gonadotropins are used in states of infertility to stimulate spermatogenesis in men and to induce ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes. Because of the high cost of gonadotropins and the need for close monitoring during their administration, they are generally reserved for women who fail to respond to other less complicated forms of treatment.
In women treated with gonadotropins and hCG, the two most serious complications are ovarian hyperstimulation syndrome and multiple pregnancies. In men, the most common adverse effect is gynecomastia.
Cosyntropin
Adrenocorticotropin
Corticotropin-releasing hormone (CRH) binds to cell-surface G protein-coupled receptors on corticotrophs of the anterior pituitary gland and stimulates corticotrophs to synthesize and release adrenocorticotropin (ACTH). ACTH stimulates the synthesis and secretion of adrenocortical steroid hormone, including glucocorticoids, androgens, and mineralocorticoids.
ACTH (corticotropin) and recombinant ACTH, cosyntropin, can be used to diagnose suspected cases of adrenal insufficiency, and specifically to assist in ascertaining whether the insufficiency is primary or secondary. They also have a role in infantile spasm (West Syndrome) and multiple sclerosis treatment. Conditions requiring physiologic replacement of glucocorticoids are usually treated with synthetic analogs of cortisol, rather than ACTH, because use of the target hormone generally allows for more precise physiologic control. Side effects are similar to that of the glucocortioids.
Atosiban
Oxytocin
Many of the known physiologic roles of oxytocin involve muscular contraction; two such effects are milk release during lactation and uterine contraction.
Oxytocin acts via specific G protein-coupled receptors. These receptors are coupled to Gq and G11 and activate the PLC-IP3-Ca2+ pathway to stimulate the release of prostaglandins and leukotrienes.
Oxytocin is administered intravenously for initiation and augmentation of labor. It also can be administered intramuscularly for control of postpartum bleeding. Severe toxicity is rare with oxytocin and includes excessive stimulation of uterine contractions, inadvertent activation of vasopressin receptors and hypotension.
Atosiban is an oxytocin antagonist that is used in the treatment of preterm labor outside of the US.
