Hypothalamic and Hypophyseal Hormones The endocrine system is controlled by the brain. Nerve cells of the hypothala- mus synthesize and release messenger substances that regulate adenohy- pophyseal (AH) hormone release or are themselves secreted into the body as hormones. The latter comprise the so- called neurohypophyseal (NH) hor- mones. The axonal processes of hypotha- lamic neurons project to the neurohy- pophysis, where they store the nona- peptides vasopressin (= antidiuretic hor- mone, ADH) and oxytocin and release them on demand into the blood. Thera- peutically (ADH, p. 64, oxytocin, p. 126), these peptide hormones are given pa- renterally or via the nasal mucosa. The hypothalamic releasing hor- mones are peptides. They reach their target cells in the AH lobe by way of a portal vascular route consisting of two serially connected capillary beds. The first of these lies in the hypophyseal stalk, the second corresponds to the capillary bed of the AH lobe. Here, the hypothalamic hormones diffuse from the blood to their target cells, whose ac- tivity they control. Hormones released from the AH cells enter the blood, in which they are distributed to peripheral organs (1). Nomenclature of releasing hor- mones: RH–releasing hormone; RIH—re- lease inhibiting hormone. GnRH: gonadotropin-RH = gona- dorelin stimulates the release of FSH (follicle-stimulating hormone) and LH (luteinizing hormone). TRH: thyrotropin-RH (protirelin) stimulates the release of TSH (thyroid stimulating hormone = thyrotropin). CRH: corticotropin-RH stimulates the release of ACTH (adrenocorticotrop- ic hormone = corticotropin). GRH: growth hormone-RH (soma- tocrinin) stimulates the release of GH (growth hormone = STH, somatotropic hormone). GRIH somatostatin inhibits release of STH (and also other peptide hormones including insulin, glucagon, and gastrin). PRH: prolactin-RH remains to be characterized or established. Both TRH and vasoactive intestinal peptide (VIP) are implicated. PRIH inhibits the release of prolac- tin and could be identical with dop- amine. Hypothalamic releasing hormones are mostly administered (parenterally) for diagnostic reasons to test AH func- tion. Therapeutic control of AH cells. GnRH is used in hypothalamic infertility in women to stimulate FSH and LH se- cretion and to induce ovulation. For this purpose, it is necessary to mimic the physiologic intermittent “pulsatile” re- lease (approx. every 90 min) by means of a programmed infusion pump. Gonadorelin superagonists are GnRH analogues that bind with very high avidity to GnRH receptors of AH cells. As a result of the nonphysiologic uninterrupted receptor stimulation, in- itial augmentation of FSH and LH output is followed by a prolonged decrease. Bu- serelin, leuprorelin, goserelin, and trip- torelin are used in patients with prostat- ic carcinoma to reduce production of testosterone, which promotes tumor growth. Testosterone levels fall as much as after extirpation of the testes (2). The dopamine D 2 agonists bromo- criptine and cabergoline (pp. 114, 188) inhibit prolactin-releasing AH cells (in- dications: suppression of lactation, pro- lactin-producing tumors). Excessive, but not normal, growth hormone re- lease can also be inhibited (indication: acromegaly) (3). Octreotide is a somatostatin ana- logue; it is used in the treatment of somatostatin-secreting pituitary tu- mors. 242 Hormones Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 243 PRH PRIH A. Hypothalamic and hypophyseal hormones GnRH TRH CRH GRH GRIH ADH Oxytocin STH(GH) ProlactinACTH ADHTSH OxytocinFSH, LH Ovum maturation; Estradiol, Progesterone Spermatogenesis; Testosterone Thyroxine Cortisol Growth Somatomedins Lactation Milk ejection Labor H 2 O Hypothalamic releasing hormones Synthesis and release of AH hormones AH-cells Synthesis Synthesis Release into blood Release into blood Neur ohypophysis Adenohypophysis (AH) Application parenteral nasal 1 90 min Released amount Pulsatile release Rhythmic stimulation AH- cell FSH LH Persistent stimulation D 2 -Receptors GnRH Leuprorelin Dopamine agonist Bromocriptine 2 3. Cessation of hormone secretion, "chemical castration" Inhibition of prolactin Buserelin Hypothalamus secretion of STH Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Thyroid Hormone Therapy Thyroid hormones accelerate metab- olism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secre- tion of TSH declines as the blood level of thyroid hormones rises; by means of this negative feedback mechanism, hor- mone production is “automatically” ad- justed to demand. The thyroid releases predominantly thyroxine (T 4 ). However, the active form appears to be triiodothyronine (T 3 ); T 4 is converted in part to T 3 , receptor affinity in target organs being 10-fold higher for T 3 . The effect of T 3 develops more rapid- ly and has a shorter duration than does that of T 4 . Plasma elimination t 1/2 for T 4 is about 7 d; that for T 3 , however, is only 1.5 d. Conversion of T 4 to T 3 releases io- dide; 150 µg T 4 contains 100 µg of io- dine. For therapeutic purposes, T 4 is cho- sen, although T 3 is the active form and better absorbed from the gut. However, with T 4 administration, more constant blood levels can be achieved because degradation of T 4 is so slow. Since ab- sorption of T 4 is maximal from an empty stomach, T 4 is taken about 1 / 2 h before breakfast. Replacement therapy of hypothy- roidism. Whether primary, i.e., caused by thyroid disease, or secondary, i.e., re- sulting from TSH deficiency, hypothy- roidism is treated by oral administra- tion of T 4 . Since too rapid activation of metabolism entails the hazard of car- diac overload (angina pectoris, myocar- dial infarction), therapy is usually start- ed with low doses and gradually in- creased. The final maintenance dose re- quired to restore a euthyroid state de- pends on individual needs (approx. 150 µg/d). Thyroid suppression therapy of euthyroid goiter (B). The cause of goi- ter (struma) is usually a dietary defi- ciency of iodine. Due to an increased TSH action, the thyroid is activated to raise utilization of the little iodine avail- able to a level at which hypothyroidism is averted. Therefore, the thyroid in- creases in size. In addition, intrathyroid depletion of iodine stimulates growth. Because of the negative feedback regulation of thyroid function, thyroid activation can be inhibited by adminis- tration of T 4 doses equivalent to the en- dogenous daily output (approx. 150 µg/d). Deprived of stimulation, the inactive thyroid regresses in size. If a euthyroid goiter has not persist- ed for too long, increasing iodine supply (potassium iodide tablets) can also be effective in reversing overgrowth of the gland. In older patients with goiter due to iodine deficiency there is a risk of pro- voking hyperthyroidism by increasing iodine intake (p. 247): During chronic maximal stimulation, thyroid follicles can become independent of TSH stimu- lation (“autonomic tissue”). If the iodine supply is increased, thyroid hormone production increases while TSH secre- tion decreases due to feedback inhibi- tion. The activity of autonomic tissue, however, persists at a high level; thy- roxine is released in excess, resulting in iodine-induced hyperthyroidism. Iodized salt prophylaxis. Goiter is endemic in regions where soils are defi- cient in iodine. Use of iodized table salt allows iodine requirements (150– 300 µg/d) to be met and effectively pre- vents goiter. 244 Hormones Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 245 B. Endemic goiter and its treatment with thyroxine A. Thyroid hormones - release, effects, degradation Thyroid Effector cell: receptor affinity L-Thyroxine, Levothyroxine, 3,5,3´,5´-Tetraiodothyronine, T 4 Liothyronine 3,5,3´-Triiodothyronine, T 3 T 3 T 4 10 1 = ~ 90 µg/Day ~ 9 µg/Day ~ 25 µg/Day I - I - I - I - Hypothalamus TRH TSH Decrease in sensivity to TRH Hypophysis "reverse T 3 " 3,3´,5´-Triiodothyronine Urine Feces Deiodinase Thyroxine Triiodothyronine Deiodination coupling Duration T 3 T 4 Day 2. 9. 10 Days30 4020 TSH Hypophysis Normal state I - T 4 , T 3 T 4 , T 3 TSH T 4 Therap. admini- stration Inhibition Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hyperthyroidism and Antithyroid Drugs Thyroid overactivity in Graves’ disease (A) results from formation of IgG anti- bodies that bind to and activate TSH re- ceptors. Consequently, there is overpro- duction of hormone with cessation of TSH secretion. Graves’ disease can abate spontaneously after 1–2 y. Therefore, initial therapy consists of reversible suppression of thyroid activity by means of antithyroid drugs. In other forms of hyperthyroidism, such as hor- mone-producing (morphologically be- nign) thyroid adenoma, the preferred therapeutic method is removal of tissue, either by surgery or administration of 131 iodine in sufficient dosage. Radioio- dine is taken up into thyroid cells and destroys tissue within a sphere of a few millimeters by emitting !-(electron) particles during its radioactive decay. Concerning iodine-induced hyper- thyroidism, see p. 244 (B). Antithyroid drugs inhibit thyroid function. Release of thyroid hormone (C) is preceded by a chain of events. A membrane transporter actively accu- mulates iodide in thyroid cells; this is followed by oxidation to iodine, iodina- tion of tyrosine residues in thyroglobu- lin, conjugation of two diiodotyrosine groups, and formation of T 4 and T 3 moieties. These reactions are catalyzed by thyroid peroxidase, which is local- ized in the apical border of the follicular cell membrane. T 4 -containing thyro- globulin is stored inside the thyroid fol- licles in the form of thyrocolloid. Upon endocytotic uptake, colloid undergoes lysosomal enzymatic hydrolysis, ena- bling thyroid hormone to be released as required. A “thyrostatic” effect can re- sult from inhibition of synthesis or re- lease. When synthesis is arrested, the antithyroid effect develops after a delay, as stored colloid continues to be uti- lized. Antithyroid drugs for long-term therapy (C). Thiourea derivatives (thioureylenes, thioamides) inhibit peroxidase and, hence, hormone syn- thesis. In order to restore a euthyroid state, two therapeutic principles can be applied in Graves’ disease: a) monother- apy with a thioamide with gradual dose reduction as the disease abates; b) ad- ministration of high doses of a thio- amide with concurrent administration of thyroxine to offset diminished hor- mone synthesis. Adverse effects of thi- oamides are rare; however, the possibil- ity of agranulocytosis has to be kept in mind. Perchlorate, given orally as the so- dium salt, inhibits the iodide pump. Ad- verse reactions include aplastic anemia. Compared with thioamides, its thera- peutic importance is low but it is used as an adjunct in scintigraphic imaging of bone by means of technetate when accumulation in the thyroid gland has to be blocked. Short-term thyroid suppression (C). Iodine in high dosage (>6000 µg/d) exerts a transient “thyrostatic” effect in hyperthyroid, but usually not in euthyr- oid, individuals. Since release is also blocked, the effect develops more rapid- ly than does that of thioamides. Clinical applications include: preop- erative suppression of thyroid secretion according to Plummer with Lugol’s solu- tion (5% iodine + 10% potassium iodide, 50–100 mg iodine/d for a maximum of 10 d). In thyrotoxic crisis, Lugol’s solu- tion is given together with thioamides and !-blockers. Adverse effects: aller- gies; contraindications: iodine-induced thyrotoxicosis. Lithium ions inhibit thyroxine re- lease. Lithium salts can be used instead of iodine for rapid thyroid suppression in iodine-induced thyrotoxicosis. Re- garding administration of lithium in manic-depressive illness, see p. 234. 246 Hormones Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 247 C. Antithyroid drugs and their modes of action A. Graves’ disease B. Iodine hyperthyroidosis in endemic goiter I - Hypophysis T 4 , T 3 TSH I - TSH- like anti- bodies T 4 , T 3 Autonomous tissue T 4 , T 3 Lysosome Storage in colloid I - T 4 - ClO 4 - Perchlorate Iodine in high dose Lithium ions I - e T 4 - Tyrosine Tyrosine I I I TG Synthesis T 4 - T 4 Peroxidase Thioamides Propylthiouracil Conversion during absorption Carbimazole Thiamazole Methimazole Release Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Glucocorticoid Therapy I. Replacement therapy. The adrenal cortex (AC) produces the glucocorticoid cortisol (hydrocortisone) and the mine- ralocorticoid aldosterone. Both steroid hormones are vitally important in adap- tation responses to stress situations, such as disease, trauma, or surgery. Cor- tisol secretion is stimulated by hypo- physeal ACTH, aldosterone secretion by angiotensin II in particular (p. 124). In AC failure (primary AC insuffiency: Addison’s disease), both cortisol and al- dosterone must be replaced; when ACTH production is deficient (secondary AC in- sufficiency), cortisol alone needs to be re- placed. Cortisol is effective when given orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by 5- to 10-fold. Aldosterone is poorly effective via the oral route; instead, the mineralocorticoid fludrocortisone (0.1 mg/d) is given. II. Pharmacodynamic therapy with glucocorticoids (A). In unphysio- logically high concentrations, cortisol or other glucocorticoids suppress all phas- es (exudation, proliferation, scar forma- tion) of the inflammatory reaction, i.e., the organism’s defensive measures against foreign or noxious matter. This effect is mediated by multiple compo- nents, all of which involve alterations in gene transcription (p. 64). Glucocorti- coids inhibit the expression of genes en- coding for proinflammatory proteins (phospholipase-A2, cyclooxygenase 2, IL-2-receptor). The expression of these genes is stimulated by the transcription factor NF !B . Binding to the glucocorti- coid receptor complex prevents translo- cation af NF !B to the nucleus. Converse- ly, glucocorticoids augment the expres- sion of some anti-inflammatory pro- teins, e.g., lipocortin, which in turn in- hibits phospholipase A2. Consequently, release of arachidonic acid is dimin- ished, as is the formation of inflamma- tory mediators of the prostaglandin and leukotriene series (p. 196). At very high dosage, nongenomic effects may also contribute. Desired effects. As anti-allergics, immunosuppressants, or anti-inflamma- tory drugs, glucocorticoids display ex- cellent efficacy against “undesired” in- flammatory reactions. Unwanted effects. With short-term use, glucocorticoids are practically free of adverse effects, even at the highest dosage. Long-term use is likely to cause changes mimicking the signs of Cushing’s syndrome (endogenous overproduction of cortisol). Sequelae of the anti-inflammatory action: lowered resistance to infection, delayed wound healing, impaired healing of peptic ul- cers. Sequelae of exaggerated glucocor- ticoid action: a) increased gluconeogen- esis and release of glucose; insulin-de- pendent conversion of glucose to trigly- cerides (adiposity mainly noticeable in the face, neck, and trunk); “steroid-dia- betes” if insulin release is insufficient; b) increased protein catabolism with atrophy of skeletal musculature (thin extremities), osteoporosis, growth re- tardation in infants, skin atrophy. Se- quelae of the intrinsically weak, but now manifest, mineralocorticoid action of cortisol: salt and fluid retention, hy- pertension, edema; KCl loss with danger of hypokalemia. Measures for Attenuating or Preventing Drug-Induced Cushing’s Syndrome a) Use of cortisol derivatives with less (e.g., prednisolone) or negligible miner- alocorticoid activity (e.g., triamcinolone, dexamethasone). Glucocorticoid activ- ity of these congeners is more pro- nounced. Glucorticoid, anti-inflamma- tory and feedback inhibitory (p. 250) ac- tions on the hypophysis are correlated. An exclusively anti-inflammatory con- gener does not exist. The “glucocorti- coid” related Cushingoid symptoms cannot be avoided. The table lists rela- tive activity (potency) with reference to cortisol, whose mineralo- and glucocor- ticoid activities are assigned a value of 1.0. All listed glucocorticoids are effec- tive orally. 248 Hormones Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 249 Unwanted Wanted A. Glucocorticoids: principal and adverse effects Inflammation redness, swelling heat, pain; scar Glucocorticoid action Mineralocorticoid action Hypertension Diabetes mellitus Cortisol unphysiologically high concentration Muscle weakness Osteo- porosis Growth inhibition Skin atrophy Tissue atrophy Triamcinolone Aldosterone Prednisolone Dexamethasone Glucose Gluconeogenesis Amino acids Protein catabolism K + Na + H 2 O e.g., allergy autoimmune disease, transplant rejection Healing of tissue injury due to bacteria, viruses, fungi, trauma 1 4 7,5 30 0,3 1 0,8 0 0 3000 Cortisol Prednisolone Triamcinolone Dexamethasone Potency Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. b) Local application. Typical adverse effects, however, also occur locally, e.g., skin atrophy or mucosal colonization with candidal fungi. To minimize systemic absorption after inhalation, derivatives should be used that have a high rate of presystemic elimination, such as beclomethasone dipropionate, flunisolide, budesonide, or fluticasone propionate (p. 14). b) Lowest dosage possible. For long- term medication, a just sufficient dose should be given. However, in attempt- ing to lower the dose to the minimal ef- fective level, it is necessary to take into account that administration of exoge- nous glucocorticoids will suppress pro- duction of endogenous cortisol due to activation of an inhibitory feedback mechanism. In this manner, a very low dose could be “buffered,” so that un- physiologically high glucocorticoid ac- tivity and the anti-inflammatory effect are both prevented. Effect of glucocorticoid adminis- tration on adrenocortical cortisol pro- duction (A). Release of cortisol depends on stimulation by hypophyseal ACTH, which in turn is controlled by hypotha- lamic corticotropin-releasing hormone (CRH). In both the hypophysis and hy- pothalamus there are cortisol receptors through which cortisol can exert a feed- back inhibition of ACTH or CRH release. By means of these cortisol “sensors,” the regulatory centers can monitor whether the actual blood level of the hormone corresponds to the “set-point.” If the blood level exceeds the set-point, ACTH output is decreased and, thus, also the cortisol production. In this way cortisol level is maintained within the required range. The regulatory centers respond to synthetic glucocorticoids as they do to cortisol. Administration of exogenous cortisol or any other glucocorticoid re- duces the amount of endogenous corti- sol needed to maintain homeostasis. Re- lease of CRH and ACTH declines ("inhi- bition of higher centers by exogenous glucocorticoid”) and, thus, cortisol se- cretion (“adrenocortical suppression”). After weeks of exposure to unphysio- logically high glucocorticoid doses, the cortisol-producing portions of the ad- renal cortex shrink (“adrenocortical atrophy”). Aldosterone-synthesizing ca- pacity, however, remains unaffected. When glucocorticoid medication is sud- denly withheld, the atrophic cortex is unable to produce sufficient cortisol and a potentially life-threatening cortisol deficiency may develop. Therefore, glu- cocorticoid therapy should always be tapered off by gradual reduction of the dosage. Regimens for prevention of adrenocortical atrophy. Cortisol secre- tion is high in the early morning and low in the late evening (circadian rhythm). This fact implies that the regu- latory centers continue to release CRH or ACTH in the face of high morning blood levels of cortisol; accordingly, sensitivity to feedback inhibition must be low in the morning, whereas the op- posite holds true in the late evening. a) Circadian administration: The daily dose of glucocorticoid is given in the morning. Endogenous cortisol pro- duction will have already begun, the regulatory centers being relatively in- sensitive to inhibition. In the early morning hours of the next day, CRF/- ACTH release and adrenocortical stimu- lation will resume. b) Alternate-day therapy: Twice the daily dose is given on alternate morn- ings. On the “off” day, endogenous corti- sol production is allowed to occur. The disadvantage of either regimen is a recrudescence of disease symptoms during the glucocorticoid-free interval. 250 Hormones Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones 251 Hypo- physis Adrenal cortex Cortisol 30 mg/day Cortisol production under normal conditions Exogenous administration Adreno- cortical atrophy Decrease in cortisol production with cortisol dose < daily production Cortisol deficiency after abrupt cessation of administration Cortisol concentration normal circadian time-course Morning dose Inhibition of endogenous cortisol production Elimination of exogenous glucocorticoid during daytime Start of early morning cortisol production A. Cortisol release and its modification by glucocorticoids CRH ACTH Hypothalamus Cessation of cortisol production with cortisol dose > daily production h0 4 8 12 16 20 24 4 8 Glucocorticoid-induced inhibition of cortisol production Glucocorticoid concentration h0 4 8 12 16 20 24 4 8 Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. [...]... Days of cycle 7 14 21 28 Monophasic preparations One-stage regimen Two-stage regimen Three-stage regimen A Oral contraceptives Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 258 Hormones Insulin Therapy Insulin is synthesized in the B- (or !-) cells of the pancreatic islets of Langerhans It is a protein (MW 5800) consisting of. .. antidiabetic Therapy of 1st choice Diagnosis: latent overt Diabetes mellitus Therapy of 2nd choice B Development of maturity-onset diabetes Membrane depolarization K+ Blockade Sulfonylurea derivatives Insulin ATP B cell Glucose Tolbutamide C Action of oral antidiabetic drugs Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 264 Hormones Drugs... preparations and blood level-time curves Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 24 260 Hormones Treatment of Insulin-Dependent Diabetes Mellitus “Juvenile onset” (type I) diabetes mellitus is caused by the destruction of insulin-producing B cells in the pancreas, necessitating replacement of insulin (daily dose approx 40 U, equivalent... Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Hormones Hypophysis FSH 257 Hypophysis 1 LH 7 14 21 28 Inhibition Minipill Ovulation Ovary Ovary Ovulation Estradiol Progesterone Intake of estradiol derivative Estradiol Penetrability by sperm cells Progesterone 1 7 14 Intake of progestin 21 Readiness for nidation 28 Day of cycle... prevention of breast cancer Raloxifen—in contrast to tamoxifen—is an antagonist at uterine estrogen receptors Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Hormones Hypothalamus 255 Hydroxyprogesterone caproate Estradiol GnRH -valerate Hypophysis 3 weeks FSH 1 week LH Medroxyprogesterone acetate -benzoate 1 2 week Duration of effect... 18 Healthy subject S no lunc h 22 24 Fea st 2 B 4 6 L 8 10 12 B 14 D Diabetic S 16 L 20 22 24 A Control of blood sugar in healthy and diabetic subjects Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license 262 Hormones Treatment of Maturity-Onset (Type II) Diabetes Mellitus In overweight adults, a diabetic metabolic condition may develop... augment tissue responsiveness by promoting the synthesis or the availability of plasmalemmal glucose transporters via activation of a transcription factor (peroxisome proliferator-activated receptor-") Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Hormones 263 Insulin binding Normal receptor number Normal diet Insulin receptor... conditions of license 256 Hormones Oral Contraceptives Inhibitors of ovulation Negative feedback control of gonadotropin release can be utilized to inhibit the ovarian cycle Administration of exogenous estrogens (ethinylestradiol or mestranol) during the first half of the cycle permits FSH production to be suppressed (as it is by administration of progestins alone) Due to the reduced FSH stimulation of tertiary... also offers a noninvasive means of inducing therapeutic abortion in early pregnancy Stimulation of ovulation Gonadotropin secretion can be increased by pulsatile delivery of GnRH (p 242) The estrogen antagonists clomiphene and cyclofenil block receptors mediating feedback inhibition of central neuroendocrine circuits and thereby disinhibit gonadotropin release Gonadotropins can be given in the form of. .. hardly affected (e.g., skeletal muscle, negative feedback inhibition of gonadotropin secretion, and libido) Finasteride can be used in benign prostate hyperplasia to shrink the gland and, possibly, to improve micturition Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved Usage subject to terms and conditions of license Hormones Hypothalamus Skeletal muscle Inhibition GnRH 253 i m Depot . Cessation of hormone secretion, "chemical castration" Inhibition of prolactin Buserelin Hypothalamus secretion of STH Lüllmann, Color Atlas of Pharmacology. 234. 246 Hormones Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Hormones