Hypothalamic and Pituitary Hormones 2 From Basophil cells

Hypothalamic and Pituitary Hormones 2

From Basophil cells: 1. Corticotrophin (ACTH): This trophic hormone stimulates synthesis & secretion of corticosteroids from all layers of adrenal cortex, esp. cortisol from zona fasciculata, and including sex steroids (esp. androgens) from zona reticularis. There is a negative feedback mechanism between plasma cortisol level and the release of CRH from hypothalamus and ACTH from anterior pituitary (Hypothalamic-pituitary- adrenal axis).

ACTH is a 39 -aminoacid peptide; its biological trophic activity resides in first 1 -24 amino acid sequence; the rest differs according to species (porcine, beef, ----etc). The sequence of 1 -14 amino acids is similar to alpha-MSH. It is released as part of large molecule POMP (pro-opio-melano-cortin) which contains ACTH, Beta-endorphin, and gamma-MSH.

Preparations: 1. Porcine ACTH (corticotrophin) 2. Cosyntropin : synthetic human ACTH (1 -24 amino acid sequence); each 0. 25 ug is equivalent to 25 IU ACTH Repository forms either complexed with gelatin or zinc hydroxide are also available Therapeutic uses: 1. Diagnosis of adrenal insufficiency(hypoadrenalism) : plasma cortisol is reduced. ACTH test is used. the cause may be either : a. Primary: Addison”s disease in which there is destruction of adrenal cortex by auto-immune mechanism. Plasma ACTH is increased due to low cortisol level.

b. Secondary: due to pituitary disease causing decreased secretion of ACTH test: Plasma cortisol is measured before and 30 and/or 60 min after cosyntropin IV. The normal response is increase in plasma cortisol to >18 ug/dl. This test is also used to test for recovery of adrenal cortex after long-term steroid therapy. 2. Rarely, ACTH replaces chronic steroid therapy in children with asthma (To avoid stunting of growth in children caused by steroids).

Adverse effects: 1. Those of long-term steroids but in addition there is hyper-androgenism causing virilism. these can occur with long-term ACTH treatment 2. Anti-bodies: causing anaphylactic reactions or resistance to ACTH. 3. Local pain, swelling, and tenderness at site of inj. : this is more with repository form with zinc hydroxide Note : No adverse effect from cosyntropin when used in ACTH test

Excess ACTH secretion is a major cause of Cushing syndrome and is caused by either basophil microadenoma (Cushing disease) or ectopic ACTH secretion by some cancers e. g. small cell bronchogenic carcinoma. Hypothalamic CRH: used to distinguish whether high ACTH Cushing syndrome is due to pituitary basophil microadenoma or ectopic ACTH secretion.

2. Gonadotrophins ( FSH and LH): These are glycoproteins; each consists of alpha- and beta- chains. Preparations (given IM) include : a. Menotropins: contain both FSH and LH , and contain either 75 or 150 IU of each; obtained from post-menopausal urine b. Urofollitropin: has FSH 75 IU, while LH is <1 IU; also obtained from post-menopausal urine c. Human chorionic gonadotrophin (h. CG): obtained from pregnant urine, and is almost identical to LH in structure; 1 unit LH is about 0. 5 IU of h. CG. It is produced by placenta; it maintains corpus luteum of pregnancy and stimulates it to produce progesterone.

Clinical uses include : 1. Anovulatory infertility due to pituitary failure: Menotropins (75 IU each of FSH and LH) are given daily for 7 -10 days, and the ovarian response is followed by estradiol plasma level, vaginal cytology and ovarian U/S. FSH level should become X 2 normal value, and LH level X 1. 5 normal value. On day 10, h. CG (5000 -10000 IU) is given to induce ovulation. This is controlled ovarian hyperstimulation. Ganirelix, a new Gn. RH antagonist, is used SC to prevent immediately premature surges of endogenous LH from pituitary. The same procedure is followed in assisted reproduction techniques e. g. in-vitro fertilization (IVF).

2. Hypogonadotrophic hypogonadism: Menotropins may be given in women. In men, h. CG is given first for 6 -12 months to stimulate development of gonads and genitalia, and to increase plasma testosterone level; this is followed by menotropins stimulate spermatogenesis. 3. Cryptorchidism: h. CG is given 2000 -4000 IU X 3/week to stimulate testosterone production and descent of testis into scrotum. This is usually done at 4 -6 years of age; if it fail, surgical orchipexy is done. 4. Sometimes h. CG is used for delayed puberty in boys. Side effects: 1. Ovarian hyperstimulation: leading to enlargement of ovarie 2. Multiple ovulation and multiple pregnancy (e. g. twins ): has an incidence of 10 -20%.

Hypothalamic Gn. RH (FSH/LH RH or LH/RH): - is a decapeptide; it stimulates release of FSH and LH. - is used IV to test for anterior pituitary function. Synthetic longer acting analogues include leuprolide, goserelin, buserelin, and nafarelin. Pulsatile administration SC of leuprolide increases Gn release , and is used to induce ovulation in women with infertility due to hypothalamic amenorrhea e. g. Kallman syndrome. Continuous administration (daily SC inj. Or SC infusion or SC pellets) of leuprolide at first stimulates Gn release followed after several days by marked inhibition due to receptor downregulation or desensitization.

This action is employed in order to: 1. Reduce testosterone production in men with prostatic carcinoma. To avoid the effects of the initial increase in testosterone on prostate, the androgen receptor antagonist flutamide is also given. (Note : carcinoma of prostate is an androgendependent cancer) 2. Reduce estrogen secretion in endometriosis.

3. Thyrotropin (TSH): is also glycoprotein with alpha- and beta- peptide chains. It stimulates iodide uptake by thyroid gland, as well as thyroid hormone synthesis and release from the gland. It is mainly used with I 131 after total thyroidectomy for functioning thyroid carcinoma (usually follicular type) in order to detect functioning metastasis and thus to help ablate them by radio-iodine.

Hypothalamic TRH: is a tri-peptide that releases TSH (and also prolactin) from pituitary. Abnormal stimulation occurs with pituitary prolactinoma, acromegally, & Cushing disease. It is mainly used diagnostically in TRH stimulation test in primary hyperthyroidism (Grave”s disease): Plasma TSH is measured before and 30 or 60 min after 400 ug TRH i. v. In Grave”s disease, no TSH increase in plasma occurs. i. e. a flat curve. Therapeutically, it was shown to improve outcome after partial spinal injury.