Hormones

Hypothalamic and Hypophyseal Hormones

The endocrine system is controlled by the brain. Nerve cells of the hypothalamus
synthesize and release messenger substances that regulate adenohypophyseal
(AH) hormone release or are themselves secreted into the body as
hormones. The latter comprise the socalled neurohypophyseal (NH) hormones.
The axonal processes of hypothalamic neurons project to the neurohypophysis,
where they store the nonapeptides vasopressin (= antidiuretic hormone,
ADH) and oxytocin and release them on demand into the blood. Therapeutically
(ADH, oxytocin), these peptide hormones are given parenterally
or via the nasal mucosa. The hypothalamic releasing hormones
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 activity they control. Hormones released
from the AH cells enter the blood, in which they are distributed to peripheral
organs.
Nomenclature of releasing hormones:
RH–releasing hormone; RIH—release inhibiting hormone.
GnRH: gonadotropin-RH = gonadorelin 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 (adrenocorticotropic hormone = corticotropin).
GRH: growth hormone-RH (somatocrinin) 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 prolactin
and could be identical with dopamine. Hypothalamic releasing hormones
are mostly administered (parenterally) for diagnostic reasons to test AH function.
Therapeutic control of AH cells. GnRH is used in hypothalamic infertility
in women to stimulate FSH and LH secretion and to induce ovulation. For this
purpose, it is necessary to mimic the physiologic intermittent “pulsatile” release
(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, initial augmentation of FSH and LH output
is followed by a prolonged decrease. Buserelin, leuprorelin, goserelin, and triptorelin
are used in patients with prostatic carcinoma to reduce production of
testosterone, which promotes tumor growth. Testosterone levels fall as much
as after extirpation of the testes. The dopamine D2 agonists bromocriptine
and cabergoline inhibit prolactin-releasing AH cells (indications:
suppression of lactation, prolactin-producing tumors). Excessive,
but not normal, growth hormone release can also be inhibited (indication:
acromegaly).
Octreotide is a somatostatin analogue; it is used in the treatment of
somatostatin-secreting pituitary tumors.

Thyroid Hormone Therapy
Thyroid hormones accelerate metabolism.Their release is regulated by
the hypophyseal glycoprotein TSH,whose release, in turn, is controlled by
the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of
thyroid hormones rises; by means of this negative feedback mechanism, hormone
production is “automatically” adjusted to demand.
The thyroid releases predominantly thyroxine (T4). However, the active form
appears to be triiodothyronine (T3); T4 is converted in part to T3, receptor affinity
in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly
and has a shorter duration than does that of T4. Plasma elimination t1/2 for T4
is about 7 d; that for T3, however, is only 1.5 d. Conversion of T4 to T3 releases iodide;
150 μg T4 contains 100 μg of iodine. For therapeutic purposes, T4 is chosen,
although T3 is the active form and better absorbed from the gut. However,
with T4 administration, more constant blood levels can be achieved because
degradation of T4 is so slow. Since absorption of T4 is maximal from an empty
stomach, T4 is taken about 1/2 h before breakfast.
Replacement therapy of hypothyroidism. Whether primary, i.e., caused
by thyroid disease, or secondary, i.e., resulting from TSH deficiency, hypothyroidism
is treated by oral administration of T4. Since too rapid activation of
metabolism entails the hazard of cardiac overload (angina pectoris, myocardial
infarction), therapy is usually started with low doses and gradually increased.
The final maintenance dose required to restore a euthyroid state depends
on individual needs (approx.150 μg/d).

Thyroid suppression therapy of euthyroid goiter. The cause of goiter
(struma) is usually a dietary deficiencyof iodine. Due to an increased
TSH action, the thyroid is activated to raise utilization of the little iodine available
to a level at which hypothyroidism is averted. Therefore, the thyroid increases
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 administration of T4 doses equivalent to the endogenous
daily output (approx. 150 μg/d). Deprived of stimulation, the
inactive thyroid regresses in size.If a euthyroid goiter has not persisted
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 provoking
hyperthyroidism by increasing iodine intake : During chronic
maximal stimulation, thyroid follicles can become independent of TSH stimulation
(“autonomic tissue”). If the iodine supply is increased, thyroid hormone
production increases while TSH secretion decreases due to feedback inhibition.
The activity of autonomic tissue, however, persists at a high level; thyroxine
is released in excess, resulting in iodine-induced hyperthyroidism.
Iodized salt prophylaxis. Goiter is endemic in regions where soils are deficient
in iodine. Use of iodized table salt allows iodine requirements (150–
300 μg/d) to be met and effectively prevents goiter.
is treated by oral administration of T4. Since too rapid activation of
metabolism entails the hazard of cardiac overload (angina pectoris, myocardial
infarction), therapy is usually started with low doses and gradually increased.
The final maintenance dose required to restore a euthyroid state depends
on individual needs (approx. 150 μg/d).

Hyperthyroidism and Antithyroid Drugs
Thyroid overactivity in Graves’ disease results from formation of IgG antibodies
that bind to and activate TSH receptors. Consequently, there is overproduction
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 hormone-producing (morphologically benign)
thyroid adenoma, the preferred therapeutic method is removal of tissue,
either by surgery or administration of 131iodine in sufficient dosage. Radioiodine
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 hyperthyroidism. Antithyroid drugs inhibit thyroid
function. Release of thyroid hormone is preceded by a chain of events. A
membrane transporter actively accumulates iodide in thyroid cells; this is
followed by oxidation to iodine, iodination of tyrosine residues in thyroglobulin,
conjugation of two diiodotyrosine groups, and formation of T4 and T3
moieties. These reactions are catalyzed by thyroid peroxidase, which is localized
in the apical border of the follicular cell membrane. T4-containing thyroglobulin
is stored inside the thyroid follicles in the form of thyrocolloid. Upon
endocytotic uptake, colloid undergoes lysosomal enzymatic hydrolysis, enabling
thyroid hormone to be released as required. A “thyrostatic” effect can result
from inhibition of synthesis or release. When synthesis is arrested, the
antithyroid effect develops after a delay, as stored colloid continues to be utilized.
Antithyroid drugs for long-term therapy. Thiourea derivatives
(thioureylenes, thioamides) inhibit peroxidase and, hence, hormone synthesis.
In order to restore a euthyroid state, two therapeutic principles can be
applied in Graves’ disease: a) monotherapy with a thioamide with gradual dose
reduction as the disease abates) administration of high doses of a thioamide
with concurrent administration of thyroxine to offset diminished hormone
synthesis. Adverse effects of thioamides are rare; however, the possibility
of agranulocytosis has to be kept in mind.
Perchlorate, given orally as the sodium salt, inhibits the iodide pump. Adverse
reactions include aplastic anemia. Compared with thioamides, its therapeutic
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.
Iodine in high dosage (>6000 μg/d) exerts a transient “thyrostatic” effect in
hyperthyroid, but usually not in euthyroid, individuals. Since release is also
blocked, the effect develops more rapidly than does that of thioamides.
Clinical applications include: preoperative suppression of thyroid secretion
according to Plummer with Lugol’s solution (5% iodine + 10% potassium iodide,
50–100 mg iodine/d for a maximum of 10 d). In thyrotoxic crisis, Lugol’s solution
is given together with thioamides and !-blockers. Adverse effects: allergies;
contraindications: iodine-induced thyrotoxicosis.
Lithium ions inhibit thyroxine release. Lithium salts can be used instead
of iodine for rapid thyroid suppression in iodine-induced thyrotoxicosis. Regarding
administration of lithium in manic-depressive illness.

Glucocorticoid Therapy
I. Replacement therapy. The adrenal cortex (AC) produces the glucocorticoid
cortisol (hydrocortisone) and the mineralocorticoid aldosterone. Both steroid
hormones are vitally important in adaptation responses to stress situations,
such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal
ACTH, aldosterone secretion by angiotensin II in particular. In
AC failure (primary AC insuffiency: Addison’s disease), both cortisol and aldosterone
must be replaced; when ACTH production is deficient (secondary AC insufficiency),
cortisol alone needs to be replaced. 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 . In unphysiologically high concentrations, cortisol or
other glucocorticoids suppress all phases(exudation, proliferation, scar formation)
of the inflammatory reaction, i.e.,the organism’s defensive measures
against foreign or noxious matter. This effect is mediated by multiple components,
all of which involve alterations in gene transcription. Glucocorticoids
inhibit the expression of genes encoding 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 glucocorticoid
receptor complex prevents translocation af NF!B to the nucleus. Conversely,
glucocorticoids augment the expression of some anti-inflammatory proteins,
e.g., lipocortin, which in turn inhibits phospholipase A2. Consequently,
release of arachidonic acid is diminished, as is the formation of inflammatory
mediators of the prostaglandin and leukotriene series . At very high
dosage, nongenomic effects may also contribute.
Desired effects. As anti-allergics, immunosuppressants, or anti-inflammatory
drugs, glucocorticoids display excellent efficacy against “undesired” inflammatory
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 ulcers. Sequelae of exaggerated glucocorticoid
action: a) increased gluconeogenesis and release of glucose; insulin-dependent
conversion of glucose to triglycerides(adiposity mainly noticeable in
the face, neck, and trunk); “steroid-diabetes” if insulin release is insufficient;
b) increased protein catabolism with atrophy of skeletal musculature (thin
extremities), osteoporosis, growth retardation in infants, skin atrophy. Sequelae
of the intrinsically weak, but now manifest, mineralocorticoid action
of cortisol: salt and fluid retention, hypertension, 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 mineralocorticoid activity (e.g., triamcinolone,
dexamethasone). Glucocorticoid activity of these congeners is more pronounced.
Glucorticoid, anti-inflammatory and feedback inhibitory actions
on the hypophysis are correlated. An exclusively anti-inflammatory congener
does not exist. The “glucocorticoid” related Cushingoid symptoms
cannot be avoided. The table lists relative activity (potency) with reference to
cortisol, whose mineralo- and glucocorticoid activities are assigned a value of
1.0. All listed glucocorticoids are effective orally.

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 .
b) Lowest dosage possible. For longterm medication, a just sufficient dose
should be given. However, in attempting to lower the dose to the minimal effective
level, it is necessary to take into account that administration of exogenous
glucocorticoids will suppress production of endogenous cortisol due to
activation of an inhibitory feedback mechanism. In this manner, a very low
dose could be “buffered,” so that unphysiologically high glucocorticoid activity
and the anti-inflammatory effect are both prevented.
Effect of glucocorticoid administration on adrenocortical cortisol production
(A). Release of cortisol depends on stimulation by hypophyseal ACTH,
which in turn is controlled by hypothalamic corticotropin-releasing hormone
(CRH). In both the hypophysis and hypothalamus there are cortisol receptors
through which cortisol can exert a feedback 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 reduces
the amount of endogenous cortisol needed to maintain homeostasis. Release
of CRH and ACTH declines ("inhibition of higher centers by exogenous
glucocorticoid”) and, thus, cortisol secretion (“adrenocortical suppression”).
After weeks of exposure to unphysiologically high glucocorticoid doses, the
cortisol-producing portions of the adrenal cortex shrink (“adrenocortical
atrophy”). Aldosterone-synthesizing capacity, however, remains unaffected.
When glucocorticoid medication is suddenly withheld, the atrophic cortex is
unable to produce sufficient cortisol and a potentially life-threatening cortisol
deficiency may develop. Therefore, glucocorticoid therapy should always be
tapered off by gradual reduction of the dosage.
Regimens for prevention of adrenocortical atrophy. Cortisol secretion
is high in the early morning and low in the late evening (circadian
rhythm). This fact implies that the regulatory 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 opposite
holds true in the late evening. a) Circadian administration: The
daily dose of glucocorticoid is given in the morning. Endogenous cortisol production
will have already begun, the regulatory centers being relatively insensitive
to inhibition. In the early morning hours of the next day, CRF/-
ACTH release and adrenocortical stimulation will resume.

b) Alternate-day therapy: Twice the daily dose is given on alternate mornings.
On the “off” day, endogenous cortisol production is allowed to occur.
The disadvantage of either regimen is a recrudescence of disease symptoms
during the glucocorticoid-free interval.

Androgens, Anabolic Steroids, Antiandrogens

Androgens are masculinizing substances. The endogenous male gonadal hormone
is the steroid testosterone from the interstitial Leydig cells of the testis.
Testosterone secretion is stimulated by hypophyseal luteinizing hormone (LH),
whose release is controlled by hypothalamic GnRH (gonadorelin). Release
of both hormones is subject to feedback inhibition by circulating testosterone.
Reduction of testosterone to dihydrotestosterone occurs in most target
organs; the latter possesses higher affinity for androgen receptors. Rapid
intrahepatic degradation (plasma t1/2 ~ 15 min) yields androsterone among
other metabolites (17-ketosteroids) that are eliminated as conjugates in the
urine. Because of rapid hepatic metabolism, testosterone is unsuitable for oral
use. Although it is well absorbed, it undergoes virtually complete presystemic
elimination. Testosterone (T.) derivatives for
clinical use. T. esters for i.m. depot injection are T. propionate and T. heptanoate
(or enanthate). These are given in oily solution by deep intramuscular injection.
Upon diffusion of the ester from the depot, esterases quickly split off the
acyl residue, to yield free T. With increasing lipophilicity, esters will tend to
remain in the depot, and the duration of action therefore lengthens. A T. ester for
oral use is the undecanoate. Owing to the fatty acid nature of undecanoic acid, this
ester is absorbed into the lymph, enabling it to bypass the liver and enter, via
the thoracic duct, the general circulation. 17-a Methyltestosterone is effective
by the oral route due to its increased metabolic stability, but because of the
hepatotoxicity of C17-alkylated androgens (cholestasis, tumors) its use should
be avoided. Orally active mesterolone is 1!-methyl-dihydrotestosterone. Transdermal
delivery systems for T. are also available.
Indications. For hormone replacement in deficiency of endogenous T.
production and palliative treatment of breast cancer, T. esters for depot injection
are optimally suited. Secondary sex characteristics and libido are maintained;
however, fertility is not promoted. On the contrary, spermatogenesis
may be suppressed because of feedback inhibition of hypothalamohypophyseal
gonadotropin secretion. Stimulation of spermatogenesis
in gonadotropin (FSH, LH) deficiency can be achieved by injection of HMG
and HCG. HMG or human menopausal gonadotropin is obtained from the urine
of postmenopausal women and is rich in FSH activity. HCG, human chorionic
gonadotropin, from the urine of pregnant women, acts like LH.
Anabolics are testosterone derivatives (e.g., clostebol, metenolone, nandrolone,
stanozolol) that are used in debilitated patients, and misused by athletes,
because of their protein anabolic effect. They act via stimulation of androgen
receptors and, thus, also display androgenic actions (e.g., virilization in females,
suppression of spermatogenesis). The antiandrogen cyproterone
acts as a competitive antagonist of T. In addition, it has progestin activity
whereby it inhibits gonadotropin secretion. Indications: in men, inhibition
of sex drive in hypersexuality; prostatic cancer. In women: treatment
of virilization, with potential utilization of the gestagenic contraceptive effect.
Flutamide, an androgen receptor antagonist possessing a different chemical
structure, lacks progestin activity. Finasteride inhibits 5!-reductase,
the enzyme converting T. into dihydrotestosterone (DHT). Thus, the androgenic
stimulus is reduced in those tissues in which DHT is the active species (e.g.,
prostate). T.-dependent tissues or functions are not or 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.

Follicular Growth and Ovulation, Estrogen and Progestin Production

Follicular maturation and ovulation, as well as the associated production of female
gonadal hormones, are controlled by the hypophyseal gonadotropins FSH
(follicle-stimulating hormone) and LH (luteinizing hormone). In the first half of
the menstrual cycle, FSH promotes growth and maturation of ovarian follicles
that respond with accelerating synthesis of estradiol. Estradiol stimulates
endometrial growth and increases the permeability of cervical mucus for
sperm cells. When the estradiol blood level approaches a predetermined setpoint,
FSH release is inhibited due to feedback action on the anterior hypophysis.
Since follicle growth and estrogen production are correlated, hypophysis
and hypothalamus can “monitor” the follicular phase of the ovarian cycle
through their estrogen receptors. Within hours after ovulation, the tertiary follicle
develops into the corpus luteum, which then also releases progesterone
in response to LH. The former initiates the secretory phase of the endometrial
cycle and lowers the permeability of cervical mucus. Nonruptured follicles
continue to release estradiol under the influence of FSH. After 2 wk, production
of progesterone and estradiol subsides, causing the secretory endometrial layer
to be shed (menstruation).The natural hormones are unsuitable
for oral application because they are subject to presystemic hepatic elimination.
Estradiol is converted via estrone to estriol; by conjugation, all three
can be rendered water soluble and amenable to renal excretion. The major
metabolite of progesterone is pregnandiol, which is also conjugated and eliminated
renally. Estrogen preparations. Depot preparations for i.m. injection are oily
solutions of esters of estradiol (3- or 17- OH group). The hydrophobicity of the
acyl moiety determines the rate of absorption, hence the duration of effect.
Released ester is hydrolyzed to yield free estradiol.
Orally used preparations. Ethinylestradiol (EE) is more stable metabolically,
passes largely unchanged through the liver after oral intake and mimics estradiol
at estrogen receptors. Mestranol itself is inactive; however, cleavage of
the C-3 methoxy group again yields EE. In oral contraceptives, one of the two
agents forms the estrogen component. (Sulfate-)conjugated estrogens
can be extracted from equine urine and are used for the prevention of postmenopausal
osteoporosis and in the therapy of climacteric complaints. Because
of their high polarity (sulfate, glucuronide), they would hardly appear
suitable for this route of administration. For transdermal delivery, an adhesive
patch is available that releases estradiol transcutaneously into the body.
Progestin preparations. Depot formulations for i.m. injection are 17-
!-hydroxyprogesterone caproate and medroxyprogesterone acetate. Preparations
for oral use are derivatives of 17!- ethinyltestosterone = ethisterone (e.g.,
norethisterone, dimethisterone, lynestrenol,desogestrel, gestoden), or of
17!-hydroxyprogesterone acetate (e.g.,chlormadinone acetate or cyproterone
acetate). These agents are mainly used as the progestin component in oral contraceptives.
Indications for estrogens and progestins include: hormonal contraception
, hormone replacement, as in postmenopausal women for prophylaxis
of osteoporosis; bleeding anomalies, menstrual complaints. Concerning
adverse effects, see p.

Estrogens with partial agonist activity (raloxifene, tamoxifene) are being
investigated as agents used to replace estrogen in postmenopausal osteoporosis
treatment, to lower plasma lipids, and as estrogen antagonists in
the prevention of breast cancer. Raloxifen—in contrast to tamoxifen—is an antagonist
at uterine estrogen receptors.

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 follicles, maturation of
follicles and, hence, ovulation are prevented. In effect, the regulatory brain
centers are deceived, as it were, by the elevated estrogen blood level, which
signals normal follicular growth and a decreased requirement for FSH stimulation.
If estrogens alone are given during the first half of the cycle, endometrial
and cervical responses, as well as other functional changes, would occur in the
normal fashion. By adding a progestin during the second half of the cycle,
the secretory phase of the endometrium and associated effects can be elicited.
Discontinuance of hormone administration would be followed by
menstruation. The physiological time course of estrogen-
progesterone release is simulated in the so-called biphasic (sequential)
preparations. In monophasic preparations, estrogen and progestin
are taken concurrently. Early administration of progestin reinforces the inhibition
of CNS regulatory mechanisms, prevents both normal endometrial
growth and conditions for ovum implantation, and decreases penetrability
of cervical mucus for sperm cells. The two latter effects also act to prevent
conception. According to the staging of progestin administration, one distinguishes
(A): one-, two-, and three-stage preparations. In all cases, “withdrawalbleeding”
occurs when hormone intake is discontinued (if necessary, by substituting
dummy tablets). Unwanted effects: An increased incidence
of thrombosis and embolism is attributed to the estrogen component in
particular. Hypertension, fluid retention, cholestasis, benign liver tumors,
nausea, chest pain, etc. may occur. Apparently there is no increased overall
risk of malignant tumors. Minipill. Continuous low-dose administration
of progestin alone can prevent conception. Ovulations are not
suppressed regularly; the effect is then due to progestin-induced alterations in
cervical and endometrial function. Because of the need for constant intake at
the same time of day, a lower success rate, and relatively frequent bleeding
anomalies, these preparations are now rarely employed.
“Morning-after” pill. This refers to administration of a high dose of estrogen
and progestin, preferably within 12 to 24 h, but no later than 72 h after coitus.
Menstrual bleeding ensues, which prevents implantation of the fertilized
ovum (normally on the 7th day after fertilization). Similarly, implantation
can be inhibited by mifepristone, which is an antagonist at both progesterone
and glucocorticoid receptors and which 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. 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 HMG and HCG .

Insulin Therapy

Insulin is synthesized in the B- (or !-) cells of the pancreatic islets of Langerhans.
It is a protein (MW 5800) consisting of two peptide chains linked by two
disulfide bridges; the A chain has 21 and the B chain 30 amino acids. Insulin is the
“blood-sugar lowering” hormone. Upon ingestion of dietary carbohydrates, it is
released into the blood and acts to prevent a significant rise in blood glucose
concentration by promoting uptake of glucose in specific organs, viz., the
heart, adipose tissue, and skeletal muscle, or its conversion to glycogen in the
liver. It also increases lipogenesis and protein synthesis, while inhibiting lipolysis
and release of free fatty acids. Insulin is used in the replacement
therapy of diabetes mellitus to supplement a deficient secretion of endogenous
hormone.
Sources of therapeutic insulin preparations (A). Insulin can be obtained
from pancreatic tissue of slaughtered animals. Porcine insulin differs
from human insulin merely by one B chain amino acid, bovine insulin by two
amino acids in the A chain and one in the B chain. With these slight differences,
animal and human hormone display similar biological activity. Compared
with human hormone, porcine insulin is barely antigenic and bovine insulin has
a little higher antigenicity. Human insulin is produced by two methods: biosynthetically,
by substituting threonine for the C-terminal alanine in the B chain of
porcine insulin; or by gene technology involving insertion of the appropriate
human DNA into E. coli bacteria. Types of preparations . As a
peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal
proteases) and thus needs to be given parenterally. Usually, insulin
preparations are injected subcutaneously. The duration of action depends
on the rate of absorption from the injection site.
Short-acting insulin is dispensed as a clear neutral solution known as
regular insulin. In emergencies, such as hyperglycemic coma, it can be given
intravenously (mostly by infusion because i.v. injections have too brief an action;
plasma t1/2 ~ 9 min). With the usual subcutaneous application, the effect
is evident within 15 to 20 min, reaches a peak after approx. 3 h, and lasts for approx.
6 h. Lispro insulin has a faster onset and slightly shorter duration of action.
Insulin suspensions. When the hormone is injected as a suspension of
insulin-containing particles, its dissolution and release in subcutaneous tissue
are retarded (rapid, intermediate, and slow insulins). Suitable particles can be
obtained by precipitation of apolar, poorly water-soluble complexes consisting
of anionic insulin and cationic partners, e.g., the polycationic protein
protamine or the compound aminoquinuride (Surfen). In the presence of zinc
and acetate ions, insulin crystallizes; crystal size determines the rate of dissolution.
Intermediate insulin preparations (NPH or isophane, lente or zinc insulin)
act for 18 to 26 h, slow preparations (protamine zinc insulin, ultralente
or extended zinc insulin) for up to 36 h. Combination preparations contain
insulin mixtures in solution and in suspension (e.g., ultralente); the plasma
concentration-time curve represents the sum of the two components.
Unwanted effects. Hypoglycemia results from absolute or relative overdosage
. Allergic reactions are rare—locally: redness at injection site,
atrophy of adipose tissue (lipodystrophy); systemically: urticaria, skin rash,
anaphylaxis. Insulin resistance can result from binding to inactivating antibodies.
A possible local lipohypertrophy can be avoided by alternating injection
sites.

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 to approx. 1.6 mg).
Therapeutic objectives are: (1) prevention of life-threatening hyperglycemic
(diabetic) coma; (2) prevention of diabetic sequelae (angiopathy with
blindness, myocardial infarction, renal failure), with precise “titration” of the
patient being essential to avoid even short-term spells of pathological hyperglycemia;
(3) prevention of insulin overdosage leading to life-threatening
hypoglycemic shock (CNS disturbance due to lack of glucose).
Therapeutic principles. In healthy subjects, the amount of insulin is “automatically”
matched to carbohydrate intake, hence to blood glucose concentration.
The critical secretory stimulus is the rise in plasma glucose level. Food intake
and physical activity (increased glucose uptake into musculature, decreased
insulin demand) are accompanied by corresponding changes in insulin
secretion (A, left track). In the diabetic, insulin could be administered
as it is normally secreted; that is, injection of short-acting insulin
before each main meal plus bedtime administration of a Lente preparation to
avoid a nocturnal shortfall of insulin. This regimen requires a well-educated,
cooperative, and competent patient. In other cases, a fixed-dosage schedule
will be needed, e.g., morning and evening injections of a combination insulin
in constant respective dosage (A). To avoid hypo- or hyperglycemias with
this regimen, dietary carbohydrate (CH) intake must be synchronized with the
time course of insulin absorption from the s.c. depot. Caloric intake is to be distributed
(50% CH, 30% fat, 20% protein) in small meals over the day so as to
achieve a steady CH supply—snacks, late night meal. Rapidly absorbable CH
(sweets, cakes) must be avoided (hyperglycemic—peaks) and replaced with
slowly digestible ones. Acarbose (an !-glucosidase inhibitor)
delays intestinal formation of glucose from disaccharides.
Any change in eating and living habits can upset control of blood sugar:
skipping a meal or unusual physical stress leads to hypoglycemia; increased
CH intake provokes hyperglycemia.Hypoglycemia is heralded by
warning signs: tachycardia, unrest,tremor, pallor, profuse sweating. Some
of these are due to the release of glucose-mobilizing epinephrine. Countermeasures:
glucose administration, rapidly absorbed CH orally or 10–20 g glucose
i.v. in case of unconsciousness; if necessary, injection of glucagon, the
pancreatic hyperglycemic hormone. Even with optimal control of blood
sugar, s.c. administration of insulin cannot fully replicate the physiological situation.
In healthy subjects, absorbed glucose and insulin released from the
pancreas simultaneously reach the liver in high concentration, whereby effective
presystemic elimination of both substances is achieved. In the diabetic,
s.c. injected insulin is uniformly distributed in the body. Since insulin concentration
in blood supplying the liver cannot rise, less glucose is extracted from
portal blood. A significant amount of glucose enters extrahepatic tissues,
where it has to be utilized.

Treatment of Maturity-Onset (Type II) Diabetes Mellitus

In overweight adults, a diabetic metabolic condition may develop (type II or
non-insulin-dependent diabetes) when there is a relative insulin deficiency—
enhanced demand cannot be met by a diminishing insulin secretion. The
cause of increased insulin requirement is a loss of insulin receptors or an
impairment of the signal cascade activated by the insulin receptor. Accordingly,
insulin sensitivity of cells declines. This can be illustrated by comparing
concentration-binding curves in cells from normal and obese individuals
(A). In the obese, the maximum binding possible (plateau of curve) is displaced
downward, indicative of the reduction in receptor numbers. Also, at low insulin
concentrations, there is less binding of insulin, compared with the control condition.
For a given metabolic effect a certain number of receptors must be occupied.
As shown by the binding curves (dashed lines), this can still be achieved
with a reduced receptor number, although only at a higher concentration of
insulin. Development of adult diabetes
(B). Compared with a normal subject, the obese subject requires a continually
elevated output of insulin (orange curves) to avoid an excessive rise of
blood glucose levels (green curves) during a glucose load. When the secretory
capacity of the pancreas decreases, this is first noted as a rise in blood glucose
during glucose loading (latent diabetes). Subsequently, not even the fasting
blood level can be maintained (manifest, overt diabetes). A diabetic condition
has developed, although insulin release is not lower than that in a healthy
person (relative insulin deficiency).Treatment. Caloric restriction to
restore body weight to normal is associated with an increase in insulin receptor
number or cellular responsiveness. The releasable amount of insulin is
again adequate to maintain a normal metabolic rate.
Therapy of first choice is weight reduction, not administration of
drugs! Should the diabetic condition fail to resolve, consideration should first be
given to insulin replacement .

Oral antidiabetics of the sulfonylurea type increase the sensitivity of B-cells
towards glucose, enabling them to increase release of insulin. These drugs
probably promote depolarization of the !-cell membrane by closing off ATP-gated
K+ channels. Normally, these channels are closed when intracellular levels
of glucose, hence of ATP, increase. This drug class includes tolbutamide (500–
2000 mg/d) and glyburide (glibenclamide) (1.75–10.5 mg/d). In some patients,
it is not possible to stimulate insulin secretion from the outset; in others,
therapy fails later on. Matching dosage of the oral antidiabetic and caloric
intake follows the same principles as apply to insulin. Hypoglycemia is the
most important unwanted effect. Enhancement of the hypoglycemic effect
can result from drug interactions: displacement of antidiabetic drug from
plasma protein-binding sites by sulfonamides or acetylsalicylic acid.

Metformin, a biguanide derivative,
can lower excessive blood glucose levels, provided that insulin is present.
Metformin does not stimulate insulin release. Glucose release from the liver is
decreased, while peripheral uptake is enhanced. The danger of hypoglycemia
apparently is not increased. Frequent adverse effects include: anorexia, nausea,
and diarrhea. Overproduction of lactic acid (lactate acidosis, lethality 50%) is
a rare, potentially fatal reaction. Metformin is used in combination with sulfonylureas
or by itself. It is contraindicated in renal insufficiency and should therefore
be avoided in elderly patients. Thiazolidinediones (Glitazones: rosiglitazone,
pioglitazone) are insulinsensitizing agents that augment tissue
responsiveness by promoting the synthesis or the availability of plasmalemmal
glucose transporters via activation of a transcription factor (peroxisome
proliferator-activated receptor-").

Drugs for Maintaining Calcium
Homeostasis At rest, the intracellular concentration
of free calcium ions (Ca2+) is kept at 0.1 μM (see p. 128 for mechanisms involved).
During excitation, a transient rise of up to 10 μM elicits contraction in
muscle cells (electromechanical coupling) and secretion in glandular cells
(electrosecretory coupling). The cellular content of Ca2+ is in equilibrium with
the extracellular Ca2+ concentration (approx. 1000 μM), as is the plasma protein-
bound fraction of calcium in blood. Ca2+ may crystallize with phosphate to
form hydroxyapatite, the mineral of bone. Osteoclasts are phagocytes that
mobilize Ca2+ by resorption of bone. Slight changes in extracellular Ca2+ concentration
can alter organ function: thus, excitability of skeletal muscle increases
markedly as Ca2+ is lowered (e.g., in hyperventilation tetany). Three
hormones are available to the body for maintaining a constant extracellular
Ca2+ concentration. Vitamin D hormone is derived
from vitamin D (cholecalciferol). Vitamin D can also be produced in the body; it is
formed in the skin from dehydrocholesterol during irradiation with UV light.
When there is lack of solar radiation, dietary intake becomes essential, cod
liver oil being a rich source. Metabolically active vitamin D hormone results
from two successive hydroxylations: in the liver at position 25 (! calcifediol)
and in the kidney at position 1 (!calcitriol = vit. D hormone). 1-Hydroxylation
depends on the level of calcium homeostasis and is stimulated by parathormone
and a fall in plasma levels of Ca2+ or phosphate. Vit. D hormone promotes
enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of
the increased Ca2+ and phosphate concentration in blood, there is an increased
tendency for these ions to be deposited in bone in the form of hydroxyapatite
crystals. In vit. D deficiency, bone mineralization is inadequate
(rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vit. D is
given; in liver disease calcifediol may be indicated, in renal disease calcitriol. Effectiveness,
as well as rate of onset and cessation of action, increase in the order vit. D. <>