By: Edward T. F. Wei PhD
Fusion of the sperm and oocyte membrane is followed by the cortical reaction and metabolic activation of the oocyte prostate oncology 360 discount 50mg penegra otc. An increase in intracellular free calcium in a periodic androgen hormone in female purchase penegra overnight, oscillatory pattern always precedes the cortical reaction and oocyte activation at fertilization mens health report purchase penegra 50mg amex, and this is believed to prostate cancer vs colon cancer purchase penegra pills in toronto be the mechanism by which the 50 prostate picture purchase penegra american express, 78 spermatozoon triggers these developmental events. A soluble sperm protein, called oscillin, has been identified in the equatorial segment of the sperm head that 79, 80 may be the signaling agent for the critical calcium oscillations. The initiation of the block to penetration of the zona (and the vitellus) by other sperm is mediated by the cortical reaction, another example of exocytosis with the 81 release of materials from the cortical granules, lysosomelike organelles that are found just below the egg surface. As with other lysosomelike organelles, these materials include various hydrolytic enzymes. Changes brought about by these enzymes lead to the zona reaction, the hardening of the extracellular layer by 82 cross-linking of structural proteins, and inactivation of ligands for sperm receptors. The initial change in this zona block is a rapid depolarization of the oocyte membrane associated with a release of calcium ions from calmodulin. The increase in intracellular calcium acts as a signal or trigger to activate protein synthesis in the oocyte. The depolarization of the membrane initiates only a transient block to sperm entry. The permanent block is a consequence of the cortical reaction and release of enzymes, also apparently triggered by the increase in calcium. The second polar body is released and leaves the egg with a haploid complement of chromosomes. The addition of chromosomes from the sperm restores the diploid number to the now fertilized egg. The chromatin material of the sperm head decondenses, and the male pronucleus is formed. The male and the female pronuclei migrate toward each other, and as they move into close proximity the limiting membranes break down, and a spindle is formed on which the chromosomes become arranged. Human gene expression (transcription) 85 begins between the 4 and 8-cell stages of preimplantation cleavage, 2–3 days after fertilization. The clinician is interested not only in how normal fertilization takes place but also in the occurrence of abnormal events that can interfere with pregnancy. It is worthwhile, therefore, to consider the failures that occur in association with in vivo fertilization. A surgical method was used to flush the uterus of regularly cycling rhesus monkeys, and 9 preimplantation embryos and 2 unfertilized eggs were recovered from 22 87 flushes. Two of the 9 embryos were morphologically abnormal and probably would not have implanted. Hendrickx and Kraemer used a similar technique in the 88 baboon and recovered 23 embryos, of which 10 were morphologically abnormal. This suggests that, in nonhuman primates, some ovulated eggs are not fertilized 89 and that many early embryos are abnormal and, in all likelihood, will be aborted. Similar findings have been reported in the human in the classic study of Hertig et al. They examined 34 early embryos recovered by flushing and examination of reproductive organs removed at surgery. Ten of these embryos were morphologically abnormal, including 4 of the 8 preimplantation embryos. Because the 4 preimplantation losses would not have been recognized clinically, there would have been 6 losses recorded in the remaining 30 pregnancies. When the loss of fertilized 91 oocytes before implantation is included, approximately 46% of all pregnancies end before the pregnancy is clinically perceived. In the postimplantation period, if only clinically diagnosed pregnancies are considered, the generally accepted figure for spontaneous miscarriage in the first trimester 92 is 15%. The fact that only 1 in 200 newborns has a chromosome abnormality attests to the powerful selection mechanisms operating in early human 52 gestation. In each ovulatory cycle, only 30% of normally fertile couples can achieve a pregnancy. Sperm penetration of the zona pellucida depends on a combination of sperm motility, an acrosomal proteinase, and binding of sperm head receptors to zona ligands. Binding of sperm head receptors and zona ligands produces an enzyme complex that induces the acrosome reaction, releasing enzymes essential for the fusion of the sperm and oocyte membranes. Fusion of the sperm and oocyte membranes triggers the cortical reaction, the release of substances from the cortical granules, organelles just below the egg cell membrane. The cortical reaction leads to the enzyme-induced zona reaction, the hardening of the zona and the inactivation of ligands for sperm receptors, producing an obstacle to polyspermy. Cell division begins promptly after fertilization; human gene expression begins between the 4 and 8-cell stages. Implantation and Placentation A normal pregnancy is, of course, impossible without successful implantation and placentation. Because there are differences among the various species, we will 93 focus on the physical and biochemical events that are relevant in human reproduction. Shortly after the 8-cell morula enters the uterine cavity about 4 days after the gonadotropin surge and 3 days after ovulation, a blastocyst (a preimplantation embryo of varying cell number, from 30 to 200) is formed. Implantation (the embedding of the blastocyst in the endometrial stroma) begins with the loss of the zona pellucida (hatching) about 1–3 days after the morula enters the uterine cavity. Preparation for Implantation the change from proliferative to secretory endometrium, described in detail in Chapter 4, is an essential part of achieving the receptive conditions required for implantation. The primary endocrine requirement is the presence of progesterone; in the monkey, implantation and pregnancy can be achieved in the absence of 94 luteal phase estrogen. This change is the histologic expression of many biochemical and molecular events. The endometrium is 10–14 mm thick at the time of implantation in the midluteal phase. By this time, secretory activity has reached a peak, and the endometrial cells are rich in glycogen and lipids. Understanding the dynamic endocrine behavior of the endometrium (Chapter 4) increases the appreciation for its active participation in the implantation process. The window of 47, 95, 96 and97 endometrial receptivity is restricted to days 16–22 of a 28-day normal cycle, and days 16–19 of cycles stimulated by exogenous gonadotropins. Endometrial receptivity is heralded by formation of pinopodes, surface epithelial microvilli that exhibit a cystic change, appearing and regressing during the window of 98 receptivity. The pinopodes may serve to absorb fluid from the uterine cavity forcing the blastocyst to be in contact with the endometrial epithelium. Even before the blastocyst adheres to the surface epithelium, but after hatching from the zona pellucida, a dialogue between the mother and the early embryo has 99 begun. Function of the corpus luteum is crucial during the first 7–9 weeks 103 of pregnancy, and luteectomy early in pregnancy can precipitate abortion. Another substance secreted very early by the preimplantation embryo is platelet-activating factor, perhaps part of the immunosuppressive activity required 105 to induce maternal tolerance of the embryo. It is not surprising that various growth factors are produced by the early embryo. Indomethacin prevents the increase in endometrial vascular permeability normally seen just prior to implantation. Additional evidence for a role by prostaglandins in the earliest stages of implantation is the finding of increased 108 concentrations at implantation sites, similar to any inflammatory response. The blastocysts of mice, rabbits, sheep, and cows produce prostaglandins, and 109 prostaglandin E2 release from human blastocysts and embryos has been demonstrated. The secretory endometrial epithelial cells are also a source of prostaglandin E2 (but not prostaglandin F2a), and its synthesis may be stimulated by the tissue response that accompanies implantation. However, decidual synthesis of prostaglandins is significantly reduced compared with proliferative and secretory endometrium, apparently a direct effect of progesterone activity and perhaps a 108 requirement in order to maintain the pregnancy. Nevertheless, prostaglandin E 2 synthesis is increased at the implantation site, perhaps in response to blastocyst 108, 110 factors. In the rabbit, platelet-activating factor also induces the 111 production of early pregnancy factor (discussed above). As discussed in Chapter 4, the many cytokines, peptides, and lipids secreted by the endometrium are interrelated through the stimulating and inhibiting actions of estrogen and progesterone, as well as the autocrine/paracrine activities of these substances on each other. The response to implantation certainly involves the many members of the growth factor and cytokine families. Implantation Implantation is defined as the process by which an embryo attaches to the uterine wall and penetrates first the epithelium and then the circulatory system of the mother to form the placenta. Implantation begins 2–3 days after the fertilized egg enters the uterus on day 18 or 97 19 of the cycle. The implantation site in the human uterus is usually in the upper, posterior wall in the midsagittal plane. Implantation consists of 3 stages: apposition, adhesion, and invasion (also called migration to denote its benign nature). Apposition and Adhesion the human blastocyst remains in the uterine secretions for approximately 1 to 3 days and then hatches from its zona pellucida in preparation for attachment. Implantation is marked initially by apposition of the blastocyst to the uterine epithelium, usually about 2–4 days after the morula enters the uterine cavity. A prerequisite for this contact is a loss of the zona pellucida, which, in vitro, can be ruptured by contractions and expansions of the blastocyst. In vivo, this activity is less critical, because the zona can be lysed by components of the uterine fluid. Nevertheless, blastocyst movement and escape from the zona pellucida appear to involve 112 cytoplasmic projections (this leads to penetrations of the zona by the trophectoderm prior to zona hatching). By this time, the blastocyst has differentiated into an inner cell mass (embryo) and trophectoderm (placenta), both essential for implantation. However, the role of interleukin-1 is less clear because mice that are deficient in the interleukin receptor have normal reproduction. The adhesion process further involves a whole collection of adhesion molecules, including integrins and selectins. The decidualized endometrium and the early 119 embryo express extracellular matrix components, especially laminin and fibronectin, which mediate cell adhesion via the adhesion molecules. Cells are fixed and supported by the extracellular matrix utilizing components such as laminin and fibronectin with attachments to these components via cell surface receptors, especially 120 the integrins. An increase in specific isoforms of laminin in decidua at the time of implantation suggests an important interaction with the invading trophoblast. Thus implantation starts with adhesion due to binding with endometrial integrins, followed by invasion (migration) of the trophoblast by proteinase degradation of the extracellular matrix. Integrins are members of a family of transmembrane cell surface receptors for collagen, fibronectin, and laminin. Integrins are utilized in cell-cell and cell-matrix interactions, contributing to cell migration, cell differentiation, and tissue structure. A cyclic change in integrin expression in the endometrial epithelial cells indicates 121 122 peak expression at the time of implantation.
In In addition to androgen hormone structure buy cheapest penegra and penegra the extent of gynecomastia androgen hormone zone discount penegra 50mg with amex, recent onset androgen hormone molecule cheap 50mg penegra otc, patients who have painful gynecomastia and in whom rapid growth prostate kegels buy generic penegra on line, tender tissue mens health rat race cheap 100 mg penegra mastercard, and occurrence in a lean surgery cannot be performed, treatment with antiestro subject should prompt more extensive evaluation. This gens such as tamoxifen (20 mg/d) can reduce pain and should include a careful drug history, measurement and breast tissue size in over half the patients. A karyotype should be obtained in men inhibitor; placebo-controlled trials with more potent aro with very small testes to exclude Klinefelter syndrome. In a randomized trial in men with established gynecomastia, anastrozole proved no more effective than placebo in reducing breast size. Except fat mass, insulin resistance, and increased risk of coronary when extreme, these clinical features may be dif cult to artery disease and mortality. Testosterone therapy of ble androgen de ciency, the laboratory evaluation is older men with sexual dysfunction and unequivocally low initiated by the measurement of total testosterone, testosterone levels improves libido, but testosterone preferably in the morning (Fig. A total testos effects on erectile function and response to selective terone level <200 ng/dL measured by a reliable assay, phosphodiesterase inhibitors have been inconsistent. An early-morning testosterone level depression scores, fracture risk, cognitive function, or >350 ng/dL makes the diagnosis of androgen de clinical outcomes in older men. In men with testosterone levels term risks of testosterone supplementation in older men between 200 and 350 ng/dL, the total testosterone remain largely unknown. In particular, physiologic level should be repeated and a free testosterone level testosterone replacement might increase the risk of should be measured. In older men and in patients prostate cancer or exacerbate cardiovascular disease. Testosterone therapy is not recommended for all older men with low testos terone levels. In older men with signi cant symptoms of Clinical Hypogonadism Consider systemic androgen de ciency who have testosterone levels below illness 200 ng/dL, testosterone therapy may be considered on an Total testosterone individualized basis and should be instituted after careful discussion of the risks and bene ts (see “Testosterone Replacement” later in the chapter). Low Borderline low Normal <200 ng/dL 200–350 ng/dL >350 ng/dL Testicular morphology, semen production, and fertility are maintained up to a very old age in men. It may cancer chemotherapeutic agents, radiation, surgical take several months for spermatogenesis to be restored; orchiectomy, or prior infectious orchitis. Unless causes therefore, it is important to forewarn patients about the of primary testicular failure are known, a karyotype potential length and expense of the treatment and to should be performed in men with low testosterone and provide conservative estimates of success rates. Occasionally, it may take 18–24 known causes of hypogonadotropic hypogonadism have months for spermatogenesis to be restored. It is not the two best predictors of success using unusual for congenital causes of hypogonadotropic gonadotropin therapy in hypogonadotropic men are hypogonadism, such as Kallmann syndrome, to be testicular volume at presentation and time of onset. Patients who became hypogonadotropic after puberty experience higher success rates than those Treatment: who have never undergone pubertal changes. The presence of a primary establish or restore fertility in patients with gonadotropin testicular abnormality, such as cryptorchidism, will de ciency of any cause. Several gonadotropin prepara attenuate testicular response to gonadotropin therapy. Increased sperm counts 172 and testicular volume have been reported in >70% of formulations should not be used for testosterone treated men, and improvements in sexual function and replacement. Hereditary angioedema due to C1 esterase virilization can be induced in >90% of patients. Cuta de ciency is the only exception to this general recom neous infections occur but are infrequent and minor. The longer the side chain, ance of sperm or pregnancy rates; both approaches are the greater the hydrophobicity of the ester and longer equally effective in inducing spermatogenesis in men with the duration of action. Within 24 h after gonadotropin injections preferable to wearing a continu intramuscular administration of 200 mg testosterone ous infusion pump. A bimonthly regimen of testosterone enanthate normal to correct features of androgen de ciency. The bone density; and gives the patient a better sense of kinetics of testosterone enanthate and cypionate are well-being. Sexual function terone serves as a prohormone and is converted to 17 and a sense of well-being are restored in androgen-de estradiol by aromatase and to 5 dihydrotestosterone cient men treated with the nongenital patch. The transdermal patches are more expen tions at the lower end of the normal male range can sive than testosterone esters. The use of testosterone restore sexual function, it is not clear whether low-normal patches may be associated with skin irritation in some testosterone levels can maintain bone mineral density individuals. The current recommendation is to restore testosterone levels to the mid-normal range. S o u r c e: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen De ciency Syndromes in Adult Men (Bhasin et al). A major concern is the potential greater agonist activity in muscle and gonadotropin suppres 175 for inadvertent transfer of the gel to a sexual partner or sion but lesser activity on the prostate. The adverse are being evaluated as anabolic therapies for functional effects include buccal ulceration and gum problems in a limitations associated with aging and chronic illness. The clinical experience with this formula Testosterone supplementation increases skeletal muscle tion is limited, and the effects of food and brushing on mass, maximal voluntary strength, and muscle power in absorption have not been studied in detail. These anabolic effects of terone undecanoate, when administered orally in oleic testosterone are related to testosterone dose and circulat acid, is absorbed preferentially through the lymphatics ing concentrations. However, the clinical mass, muscle strength, and depression indices, leading to responses are variable and suboptimal. Similarly, in glucocorticoid-treated men, Implants of crystalline testosterone can be inserted testosterone therapy should be considered to maintain in the subcutaneous tissue by means of a trocar through muscle mass and strength, and vertebral bone mineral a small skin incision. It is unknown whether testosterone therapy of erosion of the implant and absorbed into the systemic older men with functional limitations can improve physical circulation. Four to six 200-mg implants can maintain function, reduce disability, and improve health-related testosterone in the mid to high-normal range for up to quality of life. Potential drawbacks include incising the skin testosterone on prostate and cardiovascular event rates for insertion and removal, and spontaneous extrusions have encouraged the development of selective androgen and brosis at the site of the implant. However, large gens promote the differentiation of mesenchymal, mul injection volume (4 mL) is its relative drawback. A biodegradable testosterone microsphere Other indications for androgen therapy are in selected formulation provides physiologic testosterone levels for patients with anemia due to bone marrow failure (an 10–11 weeks. Because of concern about long-term adverse growth in response to androgen replacement is variable effects of supraphysiologic testosterone doses, regimens and depends on ethnicity. If the patient has a sexual part every 4–6 weeks induced azoospermia or severe oligo ner, the partner should be included in counseling zoospermia (sperm density <1 million/mL) in 99% of because of the dramatic physical and sexual changes treated men over a 1-year period. Testosterone should not be prescribed that are more potent inhibitors of gonadotropins than to men with severe symptoms of benign prostatic hyper testosterone and spare the prostate hold promise for trophy (American Urological Association symptom score their contraceptive potential. One or two 5-mg nongenital exacerbate sleep apnea because of its neuromuscular testosterone patches can be applied daily over the skin effects on the upper airway. Testosterone should not be of the back, thigh, or upper arm away from pressure administered to men with congestive heart failure with areas. Testosterone should be measured 3 months after initiating therapy to assess adequacy of therapy. In Conditions in which testosterone administration is associated with very high risk of serious adverse patients who are treated with testosterone enanthate or outcomes: cypionate, testosterone levels should be 350–600 ng/dL Metastatic prostate cancer 1 week after the injection. If testosterone levels are outside Breast cancer this range, adjustments should be made to either the dose Conditions in which testosterone administration is or the interval between injections. If testosterone levels are outside Erythrocytosis (hematocrit >50%) this range, the dose should be adjusted. Severe lower urinary tract symptoms associated with Restoration of sexual function, secondary sex charac benign prostatic hypertrophy as indicated by American teristics, and energy level and sense of well-being are Urological Association/International prostate symptom important objectives of testosterone replacement ther score >19 apy. Some hypogonadal Source: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen De ciency Syndromes in Adult men continue to complain about sexual dysfunction Men (Bhasin et al). Evaluate the patient 3 months after treatment starts and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering from any adverse effects. Monitor testosterone levels 2 or 3 months after initiation of testosterone therapy. The therapy should aim to raise serum testosterone levels into the mid-normal range. Injectable testosterone enanthate or cypionate: Measure serum testosterone levels midway between injections. Transdermal patch: Assess testosterone levels 3–12 hours after application of the patch; adjust dose to achieve testos terone levels in the mid-normal range. Buccal testosterone bioadhesive tablet: Assess levels immediately before or after application of fresh system. Transdermal gel: Assess testosterone level any time after patient has been on treatment for at least 1 week; adjust dose to achieve serum testosterone levels in the mid-normal range. Oral testosterone undecanoatea: Monitor serum testosterone levels 3–5 h after ingestion. Injectable testosterone undecanoatea: Measure serum testosterone level just prior to each subsequent injection and adjust the dosing interval to maintain serum testosterone in mid-normal range. If hematocrit is >54%, stop therapy until hematocrit decreases to a safe level; evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose. Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 years of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture, consistent with regional standard of care. Buccal testosterone tablets: Inquire about alterations in taste and examine the gums and oral mucosa for irritation. Injectable testosterone esters (enanthate and cypionate): Ask about uctuations in mood or libido. Testosterone gels: Advise patients to cover the application sites with a shirt and to wash the skin with soap and water before having skin-to-skin contact, as testosterone gels leave a testosterone residue on the skin that can be transferred to a woman or child who might come in close contact. Serum testosterone levels are maintained when the application site is washed 4–6 hours after application of the testosterone gel. Source: Reproduced from the Endocrine Society Guideline for Testosterone Therapy of Androgen De ciency Syndromes in Adult Men (Bhasin et al). Erythrocytosis tion and exacerbation of obstructive sleep apnea, and is the most frequent adverse event reported in testos increased risk of prostate cancer, though it may increase terone trials in middle-aged and older men and is also the incidence of detection rather than the actual occur the most frequent cause of treatment discontinuation rence rate. The frequency of erythrocytosis is higher adverse effects such as skin irritation with transdermal in older men than younger men and higher in hypogo patch, risk of gel transfer to a sexual partner with testos nadal men treated with injectable testosterone esters terone gels, buccal ulceration and gum problems with than in those treated with transdermal formulations, buccal testosterone, and pain and mood uctuation presumably due to the higher testosterone dose deliv with injectable testosterone esters. If hematocrit rises above 54%, testosterone therapy Hemoglobin Levels Administration of testos should be stopped until hematocrit has fallen to <50%. The most commonly used therapy increases prostate volume to the size seen in androgenic steroids include testosterone esters, nan age-matched controls but should not increase prostate drolone, stanozolol, methandienone, and methenolol. There is no evidence Athletes generally use increasing doses of multiple that testosterone replacement causes prostate cancer. A majority of ath However, androgen administration can exacerbate preex letes who abuse androgenic steroids also use other drugs isting prostate cancer. Many older men harbor microscopic that are perceived to be muscle-building or performance foci of cancer in their prostates. Elevations of liver enzymes, hepatic neo terone supplementation in androgen-de cient men are plasms, and peliosis hepatis have been reported, mostly generally <0. Upon dis Cardiovascular Risk Assessment the long continuation of exogenous androgen use, the sup term effects of testosterone supplementation on cardio pressed hypothalamic-pituitary axis may take weeks to vascular risk are unknown. During this period when testos depend on the dose (physiologic or supraphysiologic), terone levels are low, the athletes may experience sexual the route of administration (oral or parenteral), and the dysfunction, hot ushes, fatigue, and depressed mood, formulation (whether aromatizable or not). In epi mass and strength without commensurate adaptations demiologic studies, testosterone concentrations are in tendons and other connective tissues may predispose inversely related to waist-to-hip ratio and directly corre to the risk of tendon injuries.
The calmodulin molecule has 4 calcium-binding sites prostate cancer tests purchase penegra 100mg, and binding with calcium gives a helical conformation which is necessary for biologic activity prostate cancer death rate purchase penegra 100mg with mastercard. A typical animal cell contains more than 10 million molecules of calmodulin prostate 45 grams buy penegra amex, constituting about 1% of the total cell protein prostate cancer ultrasound discount 50mg penegra with amex. As a calcium regulatory protein prostate cancer 40 year old order penegra on line, it serves as an intracellular calcium receptor and modifies calcium transport, enzyme activity, the calcium regulation of cyclic nucleotide and glycogen metabolism, and such processes as secretion and cell motility. Kinase Receptors the cell membrane receptors of insulin, insulin-like growth factor, epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor are tyrosine kinases. All tyrosine kinase receptors have a similar structure: an extracellular domain for ligand binding, a single transmembrane domain, and a cytoplasmic domain. The unique amino acid sequences determine a 3-dimensional conformation that provides ligand specificity. The cytoplasmic domains respond to ligand binding by undergoing conformational changes and autophosphorylation. The structure of the receptors for insulin and insulin-like growth factor is more complicated, with two alpha and two beta-subunits, forming two transmembrane domains connected extracellularly by disulfide bridges. The receptors for the important autocrine and paracrine factors, activin and inhibin, function as serine-specific protein kinases. Kinase activation requires distinctive sequences; thus there is considerable homology among the kinase receptors in the cytoplasmic domain. Many of the substrates for these kinases are the enzymes and proteins in other messenger systems;. Thus, the kinase receptors can cross talk with other receptor regulated systems that involve the G proteins. Regulation of Tropic Hormones Modulation of the peptide hormone mechanism is an important biologic system for enhancing or reducing target tissue response. Autocrine and Paracrine Regulation Factors Growth factors are polypeptides that modulate activity either in the cells in which they are produced or in nearby cells; hence, they are autocrine and paracrine regulators. Regulation factors of this type (yet another biologic family) are produced by local gene expression and protein translation, and they operate by binding to cell membrane receptors. The receptors usually contain an intracellular component with tyrosine kinase activity that is energized by a binding-induced conformational change that induces autophosphorylation. Growth factors are involved in a variety of tissue functions, including mitogenesis, tissue and cellular differentiation, chemotactic actions, and angiogenesis. In addition to the growth factors, various immune factors, especially cytokines, modulate ovarian steroidogenesis. These factors, including interleukin-1, tumor necrosis factor, and interferon, are found in human follicular fluid and, in general, inhibit gonadotropin stimulation of steroidogenesis. For mitogenesis to occur, cells may require exposure to a sequence of growth factors, with important limitations in duration and concentrations. Growth factors are important for the direction of embryonic and fetal growth and development. In cellular differentiation, growth factors can operate in a cooperative, competitive, or synergistic fashion with other hormones. Despite the structural similarity between activin and inhibin, they function as antagonists in some systems. The activity of activin is regulated by protein binding, specifically to follistatin. Follistatin is a single-chain glycosylated peptide, structurally unrelated to inhibin and activin, that regulates the activin-inhibin system. Signaling by this family of peptides is accomplished by several receptor isoforms that are transmembrane serine kinases. The Insulin-Like Growth Factors 133 the insulin-like growth factors (also called somatomedins) are single-chain polypeptides that resemble insulin in structure and function. These factors are widespread and are involved in growth and differentiation in response to growth hormone, and as local regulators of cell metabolism. Insulin can bind to the alpha-subunit ligand-binding domain and activate the beta-subunit, which is a protein kinase. Therefore, this is a complex regulatory system that provides both endocrine signals and autocrine and paracrine functions. These proteins function as transcription factors (as are the traditional nuclear hormone receptors such as the estrogen receptor) in the complex mechanisms being unraveled by molecular biologists. The impact of the variations is to alter structure and metabolic clearance, thus affecting binding and activity. The isoforms have different molecular weights, circulating half-lives, and biologic activities. The overall activity of a glycoprotein, therefore, is due to the effects of the mixture of forms that reach and bind to the target tissue. The nonglycosylated subunit precursors of glycoprotein hormones are synthesized in the endoplasmic reticulum, followed by glycosylation. The glycosylated subunits combine and then are transported to the Golgi apparatus for further processing of the carbohydrate component. The protein moiety binds to specific target tissue receptors, while the carbohydrate moiety plays a critical role in coupling the hormone-receptor complex to adenylate cyclase (perhaps by determining the necessary conformational structure). The preciseness of the chemical make up of the tropic hormones is an essential element in determining the ability of the hormone to mate with its receptor. The three-dimensional structure and the active conformation of the subunits are maintained by internal disulfide bonds. The b-chains (or the b-subunits) differ in both amino acid and carbohydrate content, conferring the specificity inherent in the relationship between hormones and their receptors. Furthermore, the three dimensional structure of the b-subunit, accomplished by folding the subunit by the formation of the disulfide bonds, is an important 145 conformational step that is essential for assembly with the a-subunit. This conformational change is not completed until the subunits are fully united to produce the final whole hormone. The carbohydrate components of the glycoproteins are composed of fructose, galactose, mannose, galactosamine, glucosamine, and sialic acid. Genes for tropic hormones contain promoter and enhancer or inhibitor regions located in the 5 flanking regions upstream from the transcription site. The protein cores of the two glycoprotein subunits are the products 146 of distinct genes. The a-subunit gene is expressed in several different cell types, but the b-subunit genes are restricted in cell type. The a-subunit gene requires the activation of distinct regulatory elements in thyrotrope and gonadotrope cells, as well as in the placenta. It is the activation of these cell-specific elements that produces tissue specificity for a-gene expression. Protein kinase regulation of the a promoter is a principal part of the overall mechanism. This pituitary process is influenced by multiple factors, including growth factors and gonadal steroids. Only primates and horses have been demonstrated to have genes for the b-subunit of chorionic gonadotropin. The clinical significance of this mutation is not known; however, routine immunoassays can provide falsely low readings because this variant is not detected. Although the b-subunit specifies the biologic activity of an individual glycoprotein, the combination of the a and b-subunits is necessary for full hormonal expression. Neither subunit alone can effectively bind to the receptor with high affinity or exert biologic effect. In other words, binding and activation occur only when the hormone is in the combined a-b form. Variations in Carbohydrate the glycopeptide hormones can be found in the pituitary existing in a variety of forms, differing in their carbohydrate (oligosaccharides) make up. This heterogeneity in structure (which is also associated with heterogeneity in charge) represents a mechanism under endocrine control that modulates half-lives and bioactivity. Certain clinical conditions may be associated with alterations in the usual chemical structure of the glycopeptides, resulting in an interference with the ability to bind to receptors and stimulate biological activity. In addition to deglycosylation and the formation of antihormones, gonadotropins can be produced with an increased carbohydrate content. A low-estrogen environment in the pituitary gland, for example, favors the production of so-called big gonadotropins, gonadotropins with an 157 increased carbohydrate component and, as a result, decreased biological activity. Immunoassay in these situations may not reveal the biologic situation; an immunoassay sees only a certain set of molecules but not all. The highest values are during the 158 midcycle surge and in postmenopausal women (including women with premature ovarian failure). The carbohydrate component, therefore, affects target tissue response in two ways: 1) metabolic clearance and half-life and 2) biologic activity. The latter action focuses on two functions for the hormone-receptor complex: binding and activation. One structural domain is important for binding and another for triggering the biologic response. Carbohydrate residues, especially the sialic acid residues, are less important in binding. Indeed, experimental data indicate that the carbohydrate 159 chains have no role in the binding of gonadotropins to their receptors. Nevertheless, removal of the carbohydrate moiety of either subunit diminishes gonadotropic activity. Therefore, the carbohydrate component affects the biologic activity of the hormone-receptor complex after binding. Specific studies indicate that the 160 carbohydrate component plays a critical role in activation (coupling) of the adenylate cyclase system. However, clearance of gonadotropins as measured by half-lives is not explained totally by carbohydrate differences. Differences in amino acid sequences also contribute, and most importantly, the stability of the complete hormone (resisting dissociation into the rapidly cleared subunits) is a major factor. Heterogeneity of Prolactin 162 In most mammalian species, prolactin is a single-chain polypeptide of 199 amino acids, 40% similar in structure to growth hormone and placental lactogen. All three hormones are believed to have originated in a common ancestral protein about 400 million years ago. At first, differences in prolactin were observed based on size, leading to the use of terms such as little, big, and the wonderfully sophisticated term, big big prolactin. Further chemical studies have revealed structural modifications that include glycosylation, phosphorylation, and variations in binding and charge. This heterogeneity is the result of many influences at many levels: transcription, 163, 164 translation, and peripheral metabolism. Most, if not all, variants of prolactin are the result of posttranslational modifications. Little prolactin probably represents a splicing variant resulting from the proteolytic deletion of amino acids.
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