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Uterine Relaxants

  UTERINE RELAXANTS   Many risk factors are associated with the triggering of premature labor, that is, labor that begins before the end of week 37 of gestation. These include maternal smoking or drug abuse, lack of prenatal care, multiple gestation, placental abnormalities, infection of the fetal membranes, cervical incompetence, and previous preterm birth. Although most episodes are of unknown origin, premature labor can develop spontaneously or may follow early rupture of fetal membranes, perhaps as a result of a genetically associated abnormality.   Uterine relaxants ( tocolytic drugs ) are administered where prolonged intrauterine life would greatly benefit the fetus or would permit additional time to allow treat-ment with drugs such as corticosteroids, which promote the production of fetal lung surfactant. Tocolytics are also used when temporary uterine relaxation is be de-sirable (e.g., intrauterine fetal resuscitation). While hy-dration, bed rest, and sedation have been used to
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Characterization of Plasma Androgens

  CHARACTERIZATION OF PLASMA ANDROGENS   In males,  testosterone  is the principal circulating andro-gen, and the testes are the principal source. Although the adrenals are capable of androgen synthesis, less than 10% of the circulating androgens in men are pro-duced in the adrenals. Testosterone is synthesized by Leydig cells of the testes at the rate of about 8 mg/24 hours, providing a plasma concentration of 0.5 to 0.6 g/dL. In females, the ovaries contribute approxi-mately one-third of the total androgens synthesized, while the adrenals contribute the rest.   Androstenedione, dehydroepiandrosterone  (DHEA),   and  dehydroepiandrosterone sulfate  (DHEA-S) are other mildly androgenic compounds of secondary im-portance in males and females. The gonads and the ad-renal cortex are capable of secreting androstenedione and DHEA, while DHEA-S is secreted primarily by the adrenal.   Concentrations of plasma testosterone and other androgens vary throughout the day in both sexes; whether such
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Sex Hormone–Binding Proteins

  SEX HORMONE–BINDING PROTEINS   Circulating testosterone is reversibly bound to two major plasma proteins,  albumin  and  gamma globulin.  Binding to albumin is a relatively nonspecific low-affinity and high-capacity association. In contrast, binding to the specific  γ -globulin fraction, called  sex hormone–binding   globulin  ( SHBG ), is a high-affinity steroid-specific in-teraction. Under physiological conditions, 98% of testosterone is protein bound, 40% to albumin and 58% to SHBG. Thus, 2% or less of circulating testosterone is unbound or free.  Free testosterone reflects the amount   that is biologically active and available for interaction with peripheral target cells.   SHBG levels are known to be influenced by a variety of clinical conditions. In females, the high estrogen levels of pregnancy or the use of oral contraceptives result in in-creased SHBG concentrations. In males, elevated levels of SHBG are seen most commonly in individuals with liver cirrhosis or during normal
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Steroidogenesis

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  STEROIDOGENESIS   The main steroidogenic components of the testis are the interstitial cells of Leydig found between the seminifer-ous tubules. The principal secretory product of Leydig cells, testosterone, is not stored to any significant degree within these cells. Biochemical studies of Leydig cell steroidogenic function have shown that  testosterone   synthesis begins with acetate derived either from glucose or products of lipid metabolism.  Acetate is converted   to cholesterol through numerous reactions in or on the smooth endoplasmic reticulum. Cholesterol, once formed, is stored in lipid droplets in an esterified form. The cholesterol required for steroidogenesis is trans-ferred into the mitochondria, where the side chain is cleaved by enzymes on the inner membranes to form pregnenolone.  This reaction is the rate-limiting step in   testosterone biosynthesis and is the step stimulated by luteinizing hormone (LH).  Pregnenolone is then re-turned to the cytoplasm, where it serve
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Regulation of Plasma Testosterone

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  REGULATION OF PLASMA TESTOSTERONE     The regulation of plasma testosterone is accomplished through a dynamic feedback interaction among the hy-pothalamus, pituitary, and testis (Fig. 63.2). The hypothal-amus synthesizes and releases gonadotropin releasing hormone (GnRH) into the hypothalamic–hypophyseal portal system. Pulsatile release of GnRH stimulates the release of the pituitary gonadotropins LH and follicle-stimulating hormone (FSH).  LH and FSH then reach the  testes, where they regulate testosterone synthesis and spermatogenesis, respectively. The resultant increases in serum testosterone levels exert a negative feedback at both the hypothalamic and the pituitary levels.   The hypothalamus releases GnRH in a pulsatile manner. The pulse frequency is sex specific, with males exhibiting a 120-minute frequency and females exhibit-ing a 60- to 90-minute frequency. The pulsating levels of GnRH from the pituitary modulate LH and FSH re-lease. Androgens and estrogens can modulate go-
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Androgen: Mechanism of Action

  MECHANISM OF ACTION   Given the wide spectrum of androgen actions, it is rea-sonable to expect the intracellular processes mediating these diverse effects to vary among target tissues. The currently accepted hypothesis of androgen action in male sex accessory organs is depicted in Fig. 63.4. Testosterone diffuses from the blood across the plasma membrane of the sex accessory organ cell, where it is rapidly metabolized to DHT and androstanediol.  In   many sex accessory organs, DHT, rather than testos-terone, is the primary intracellular androgen  and is more   potent than testosterone. Once formed, DHT preferen-tially binds to a receptor protein in the nucleus. This DHT–receptor complex is subsequently activated and binds to proteins on the nuclear matrix. Following this interaction, RNA synthesis results in enhanced protein synthesis and cellular metabolism. If sufficient andro-gen stimulation occurs, DNA synthesis and cellular di-vision begin.   Non-sex accessory tissues also are t
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Androgens: Pharmacological Actions

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  PHARMACOLOGICAL ACTIONS   Androgens produce both virilizing and protein anabolic actions (Table 63.1). The virilizing actions of testos-terone include irreversible effects that occur during em-bryogenesis, that is, those that induce differentiation of the central nervous system and male reproductive tracts, and the  excitatory actions  at puberty that are  responsible for secondary sexual development.   In addi-tion to the effects on male reproductive function, an-drogens influence a number of other systems, many of which are associated with masculinity. These actions in-clude the growth of male-pattern facial, pubic, and body hair, the lower vocal pitch resulting from a thickening  and lengthening of the vocal cords, and a significant (30%) increase in the rate of long bone growth.   Androgens also terminate long bone growth by induc-ing closure of the epiphyses. The degree of virilization and timing of puberty also affect peak bone density and risk of osteoporosis in males.   The p
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