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Valentin Fuster, MD, PhD, MACC

• Director, Mount Sinai Heart
• Mount Sinai Hospital
• Professor of Medicine
• Mount Sinai School of Medicine
• New York, New York

Febrile superior activity to gefitinib in clinical trials in nonneutropenia refers to the clinical presentation of fever small cell lung cancer erectile dysfunction family doctor purchase top avana 80 mg fast delivery. Mortality from uncontrolled infection In addition to the p210bcr-abl kinase erectile dysfunction with normal testosterone levels buy top avana 80mg on-line, imatinib also has varies inversely with the neutrophil count erectile dysfunction medication canada buy top avana overnight delivery. Imatinib has found clinical empirical coverage with antibiotics for the duration of utility in these neoplasms previously refractory to neutropenia (Chap erectile dysfunction over 65 purchase 80 mg top avana. In the absence of any originating site erectile dysfunction caused by anabolic steroids cheap 80mg top avana fast delivery, a broadly activity against the raf serine-threonine protein kinase as acting -lactam with anti-Pseudomonas activity erectile dysfunction in diabetes medscape top avana 80 mg on-line, such as well. It causes prominent responses as comycin to cover potential cutaneous sites of origin (until well as stabilization of disease in renal cell cancers and these are ruled out or shown to originate from methicillingastrointestinal stromal tumors. Side effects for both sensitive organisms) or metronidazole or imipenem for agents are mostly acceptable, with fatigue and diarrhea abdominal or other sites favoring anaerobes refiects modiencountered with both agents. Febrile neutropenic patients can be concomitant chemoradiation treatment, particularly stratified broadly into two prognostic groups. The first, those with thoracic neoplasms, likewise are not generally with expected short duration of neutropenia and no recommended for treatment. A less favorable progat the time fever develops, pneumonia, profound neunostic group are patients with expected prolonged neutropenia (<0. The settings plants, although proper head-to-head comparisons with in which their use has been proved effective are limited. In conCertain cytokines in clinical investigation have shown trast, patients with myeloproliferative states may have an ability to increase platelets. Careful review of medication lists to prevent platelet counts are small, and it is associated with side exposure to nonsteroidal anti-infiammatory agents and effects such as headache, fever, malaise, syncope, cardiac maintenance of clotting factor levels adequate to suparrhythmias, and fiuid retention. Lorazepam (Ativan) is zomib, with minimal risk (<10%) afforded by treatment a short-acting benzodiazepine that provides an anxiolytic with antibodies, bleomycin, busulfan, fiudarabine, and effect to augment the effectiveness of a variety of agents vinca alkaloids. Regimens that include fiuorouracil infusions and/or Females experience amenorrhea with anovulation after irinotecan may produce severe diarrhea. Similar to the alkylating agent therapy; they are likely to recover norvomiting syndromes, chemotherapy-induced diarrhea mal menses if treatment is completed before age 30 but may be immediate or can occur in a delayed fashion up unlikely to recover menses after age 35. Hormone replacement therapy be considered for patients not responding to loperamide. For those patients who have had Mucositis a hormone-sensitive tumor primarily treated by a local Irritation and infiammation of the mucous membranes modality, conventional practice would counsel against horparticularly affiicting the oral and anal mucosa, but potenmone replacement, but this issue is under investigation. All agents tend to have increased risk the proliferating cells at the base of the mucosal squamous of adverse outcomes when administered during the first epithelia or in the intestinal crypts. To p ical therapies, trimester, and strategies to delay chemotherapy, if possiincluding anesthetics and barrier-creating preparations, ble, until after this milestone should be considered if the may provide symptomatic relief in mild cases. Patients in their secor keratinocyte growth factor, a member of the fibroblast ond or third trimester can be treated with most regimens growth factor family, is effective in preventing severe for the common neoplasms affiicting women in their mucositis in the setting of high-dose chemotherapy with childbearing years, with the exception of antimetabolites, stem cell transplantation for hematologic malignancies. It particularly antifolates, which have notable teratogenic or may also prevent mucositis from radiation. The need for anticancer chemotherapy per se is infrequently a clear Alopecia basis to recommend termination of a concurrent pregnancy, although each treatment strategy in this circumChemotherapeutic agents vary widely in causing alopestance must be tailored to the individual needs of the cia, with anthracyclines, alkylating agents, and topoisopatient. Chronic effects of cancer treatment are reviewed merase inhibitors reliably causing near-total alopecia in Chap. Theoretically, couraged, particularly during treatment with curative biologic approaches should refiect a bell-shaped doseintent of neoplasms such as leukemia or lymphoma, or in response curve where the maximum biologic effect is adjuvant breast cancer therapy. However, empirical trial and error scalp can certainly harbor micrometastatic or dissemihas led to the discovery that a number of biologic treatnated disease. The duration of these effects varies with age genes, or antigen expression) on the part of the tumor and sex. This may be conmens are effectively sterile, whereas fertility usually trasted with the more narrowly defined antiproliferative returns after regimens that include cisplatin, vinblastine, or apoptotic response that is the ultimate goal of the or etoposide and after bleomycin for testicular cancer. However, there is much commonality in the strategies to evaluate and given back to the patient. Short periods removed from the the immune system: (1) they are often only subtly differpatient permit the cells to overcome the tumorent from their normal counterparts; (2) they are capable induced T cell defects, and such cells traffic and of downregulating their major histocompatibility comhome to sites of disease better than cells that have plex antigens, effectively masking them from recognition been in culture for many weeks. Individual centers by T cells; (3) they are inefficient at presenting antigens to have successful experiences with one or the other the immune system; (4) they can cloak themselves in a approach but not both, and whether one is superior protective shell of fibrin to minimize contact with surto the other is not known. Tumor vaccines are aimed at boosting T cell immusoluble molecules, including potential immune targets, nity. The finding that mutant oncogenes that are that can distract the immune system from recognizing the expressed only intracellularly can be recognized as tumor cell or can kill the immune effector cells. Some of targets of T cell killing greatly expanded the possibilthe cell products initially polarize the immune response ities for tumor vaccine development. However, major difficulties remain in getting prevent their activation and cytotoxic activity. Cancer the tumor-specific peptides presented in a fashion to treatment further suppresses host immunity. Tumors themselves are very poor at strategies are being tested to overcome these barriers. Priming is best accomplished by professional antigen-presenting cells (denthe strongest evidence that the immune system can dritic cells). Thus a number of experimental strategies are exert clinically meaningful antitumor effects comes from aimed at priming host T cells against tumor-associated allogeneic bone marrow transplantation. Such an approach mediate impressive antitumor effects (graft-versus-tumor has been documented to eradicate microscopic resideffects). Three types of experimental interventions are ual disease in follicular lymphoma and give rise to being developed to take advantage of the ability of tumor-specific T cells. Allogeneic T cells are transferred to cancer-bearing particular tumor antigens and delivered as a vaccine. In a variation on the theme of adoptive transrecovery after allogeneic bone marrow transplantafer, the tumor vaccine may be given to the normal tion, and as pure lymphocyte transfusions following bone marrow and lymphoid cell donor of an alloimmunosuppressive (but not myeloablative) therapy geneic transplant so that the donor immune system (so-called mini-transplants). In each of these sethas more cells capable of recognizing the tumor tings, the effector cells are donor T cells that recogspecifically. Vaccines against viruses that cause cancers nize the tumor as being foreign, probably through are safe and effective. The main risk hepatocellular carcinoma, and a tetravalent human of such therapy is the development of graft-versuspapilloma virus vaccine prevents infection by virus host disease because of the minimal difference types currently accounting for 70% of cervical canbetween the cancer and the normal host cells. These vaccines are ineffective at treating patients approach has been highly effective in certain who have developed a virus-induced cancer. Autologous T cells are removed from the tumorof activity against multiple myeloma, certain lymbearing host, manipulated in several ways in vitro, phomas, and melanomas. BevaIn general, antibodies are not very effective at killing cizumab has a number of side effects of medical significancer cells. Because the tumor seems to infiuence the cance, including hypertension, proteinuria, hemorrhage, host toward making antibodies rather than generating and gastrointestinal perforations with or without prior cellular immunity, it is inferred that antibodies are easier surgeries. Many patients can be shown Conjugation of antibodies to drugs and toxins was to have serum antibodies directed at their tumors, but discussed earlier; conjugates of antibodies with isothese do not appear to infiuence disease progression. Other conjugates are associated with Clinical antitumor efficacy has been obtained using problems that have not yet been solved. Its antitumor effects appear when used to augment the activity of an additional to be antagonized in vitro by thymidine, suggesting chemotherapy program, and in the primary treatment of that de novo thymidylate synthesis is also affected. It evidence of antitumor effect when used alone, but when produces fever, fatigue, a fiulike syndrome, malaise, combined with chemotherapeutic agents it improves the myelosuppression, and depression and can induce clinimagnitude of tumor shrinkage and time to disease procally significant autoimmune disease. Its biologic the capacity of the antibody to alter delivery and tumor activity is to promote the growth and activity of T cells uptake of the active chemotherapeutic agent. In addition, distinct syndromes have durable, unlike any other treatment for these tumors. Principles of Internal Medicine, and some of their material has 373 Patients may require blood pressure support and intenbeen incorporated into this chapter. J Clin Oncol No gene therapy has been approved for routine clinical 24:3187, 2006 use. For example, a squamost deaths from acute leukemia and half of the deaths mous cell carcinoma may cause local invasion of the from lymphoma are caused directly by infection. With epidermis, which allows bacteria to gain access to the more intensive chemotherapy, patients with solid tumors subcutaneous tissue and permits the development of celhave also become more likely to die of infection. The artificial closing of a normally patent orifice nately, an evolving approach to prevention and treatcan also predispose to infection: Obstruction of a ureter ment of infectious complications of cancer has decreased by a tumor can cause urinary tract infection, and rates of infection-associated mortality and will probably obstruction of the bile duct can cause cholangitis. Use of antibiotics for afebrile neutropenic patients as prophylaxis has been necessary in refractory cases. Even after curative therapy for the underlying onset of fever or other symptoms of bacterial infection. The isms should depend on the type of cancer diagnosed splenectomized patient should be counseled about the (Table 28-3). Pertussis vaccines have not been recommended for people >6 years of age in the past. It is anticipated that future vaccines will include more serotypes and will be recommended for adults. In addition to exhibiting susceptibility to cercumscribed in normal hosts, it may spread rapidly in tain infectious organisms, patients with cancer are likely to neutropenic patients. A tiny break in the skin may lead to manifest their infections in characteristic ways. A dramatic response to an infection Skin lesions are common in cancer patients, and the that might be trivial in a normal host can mark the appearance of these lesions may permit the diagnosis of first sign of leukemia. Innocent-looking macules or papules may be received antibiotics for other reasons may develop celthe first sign of bacterial or fungal sepsis in immunolulitis with unusual organisms. Early treatment, even of innohost, a macule progresses rapidly to ecthyma gangrenocent-looking lesions, is essential to prevent necrosis and sum, a usually painless, round, necrotic lesion consisting loss of tissue. Debridement to prevent spread may someof a central black or gray-black eschar with surrounding times be necessary early in the course of disease, but it erythema. The disease is characterized Candidemia is also associated with a variety of skin by the presence of leukocytes in the lower dermis, with conditions and commonly presents as a maculopapular edema of the papillary body. Punch biopsy of the skin may be the best method is usually seen in neutropenic patients with cancer, most for diagnosis. Papules related to Escherichia coli bacteremia in a neutropenic patient with acute lymphocytic leukemia. Some Staphylococcus epidermidis catheter-associated infections can be treated with Staphylococcus aureus antibiotics; in others the catheter must be removed Viridans Streptococcus (Table 28-5). Failure to remove catheters Pseudomonas aeruginosa under these circumstances may result in extensive celNon-aeruginosa Pseudomonas spp. Most authorities recommend Gram-positive bacilli treatment (usually with vancomycin) for an exit-site Diphtheroids infection caused by a coagulase-negative Staphylococcus. The lesions are most common on larly, isolation of Bacillus, Corynebacterium, and Mycobacthe face, neck, and arms.

However erectile dysfunction vacuum purchase top avana 80mg otc, for early vulvar disease a subgroup has been identified in whom radiotherapy is recommended erectile dysfunction protocol book review purchase top avana discount. However vasculogenic erectile dysfunction causes top avana 80mg discount, according to some gynaecological oncologists vascular erectile dysfunction treatment discount top avana online amex, there is no evidence to support the pathological parameters quoted in the guidelines erectile dysfunction treatment with exercise purchase top avana 80 mg without prescription. These experts state that evidence for post-operative radiotherapy exists only in patients with > 1 macro-metastasis erectile dysfunction drugs prostate cancer discount top avana 80 mg with mastercard, > 2 micro metastases, extranodal spread or margins < 5mm. These patients are considered to be at intermediate or high risk for recurrence and significant failure rates occur in the absence of radiotherapy (75) (85) (86) (87). Intermediate and high risk patients are defined as patients with 2 unilateral lymph nodes, tumours of > 2 cm with 1 positive node and lesions > 8 cm with no positive nodes. Incidence of post-surgical recurrence the treatment of recurrent vulvar cancer has not been standardized due to the various ways in which recurrence may present. Two expert reviewers in this report both suggested that surgery is almost always the treatment of choice for local recurrence but nodal recurrences will almost always require radiation (either alone or in combination with surgery). Three patients developed local recurrence and all were successfully salvaged with further radical surgery. The development of distant metastases is rare without local recurrence and therefore a branch on the decision tree has been omitted. The omission of a branch on the decision tree corresponding to those who did not receive radiotherapy at initial treatment or at recurrence, and who subsequently developed isolated distant recurrence amenable to palliation with radiotherapy (such as brain or bone metastases) is unlikely to alter the overall estimate for optimal radiotherapy utilisation. Sensitivity Analysis Sensitivity analysis allows the assessment of the impact of changing the value of the variables on the overall end result. For the gynaecological decision tree, one data item was identified as being uncertain. In endometrial cancer, no data could be identified to estimate the proportion of early stage endometrial cancer patients who undergo a lymph node dissection. To assess the impact of this uncertainty on the overall estimate of the need for radiotherapy in all gynaecological cancers, a sensitivity analysis was performed for each of the variables. Once the decision trees for all tumours are completed, a tornado analysis will be performed whereby the impact that each of these variables has on the overall estimate of the proportion of cancer patients needing radiotherapy will be examined. The graphs below show that the optimal proportion of gynaecological cancer patients who should receive radiotherapy based on evidence and incidence of attributes for radiotherapy is 35%. This proportion could vary from a low of 31% to a high of 39% depending on the proportion of patients undergoing endometrial cancer surgery who also have a lymph node dissection (varied between the extremes of 10% to 90%). Tornadodiagram of sensitivityanalysisforgynaecologicalcancer T ornado Diagram at G ynaecancer proportionofendometrialcancerpatientsundergoingnodedissection:0. The optimal utilisation rates for the five gynaecological tumour sub-sites are shown in Table 8. Table 8: Optimal radiotherapy utilisation rates by gynaecological subtype Tumour Sub% of Overall optimal Proportion of all site gynaecological radiotherapy utilisation rate cancer patients cancer for sub-site (%) that should receive radiotherapy Cervix 23 58 0. Consensus Statement: National Institutes of Health consensus development conference statement on cervical cancer. The palliation of brain metastases in a favorable patient population: a randomized clinical trial by the radiation therapy oncology group. Multivariate analysis of the histopathologic prognostic factors of cervical cancer in patients undergoing radical hysterectomy. Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. Definition and prognostic significance of microinvasion in the uterine cervix squamous lesion. A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer. Prognostic value of performance status assessed by patients themselves, nurses, and oncologists in advanced non-small cell lung cancer. Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery. The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the endometrium. Risk factors for recurrence in clinically early endometrial carcinoma: an analysis of 183 consecutive cases. Recurrent adenocarcinoma of the endometrium: a clinical and histopathological study of 379 patients. Significance of true surgical pathologic staging: a Gynecologic Oncology Group study. The role of adjuvant radiotherapy in carcinoma of the endometrium results in 550 patients with pathologic Stage I disease. Excellent long-term survival and absence of vaginal recurrences in 332 patients with lowrisk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: report of a prospective trial. The relationship of local and distant failure from endometrial cancer: defining a clinical paradigm. Recurrent endometrial cancer after surgery alone: results of salvage radiotherapy. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. Postoperative radiotherapy and surgery in Stage I endometrial carcinoma: a 10-year experience. The effect of a single fraction compated to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Groin dissection versus groin radiation in carcinoma of the vulva: a gynecologic oncology group study. Radiation therapy in management of carcinoma of the vulva with emphasis on conservation therapy. Radical resection of vulvar malignancies: a paradigm shoft in surgical approaches. Management of regional lymph nodes and their prognostic significance in vulvar cancer. Genitourinary Cancers (excluding prostate cancer) Renal Cancer Table 1:R enalC ancer. Th e incidence ofattributes used to define indications forradioth erapy K ey Populationor Attribute Proportionof Q ualityof R eferences N otes subpopulationof populationwith inform ation interest thisattribute A Allregistrycancers R enalcancer 0. Indications for radiotherapy the primary treatment modality for renal cancer is radical surgical resection. The decision tree has not included positive margins as a reason for giving radiotherapy. There are also other less common clinical scenarios that may be considered for radiotherapy such as symptomatic lung metastases. However, these situations are rare enough that their omission from the tree is unlikely to have a significant impact on the overall radiotherapy utilisation rate for renal cancer. Overall incidence Renal cancer comprises 3% of all cancers according to the Australian Institute of Health and Welfare statistics for 1998. Stage proportions the treatment of renal cancer is predominantly radical surgery (total or partial nephrectomy) in patients with no metastatic disease. Surgery is also sometimes indicated in patients with limited metastatic disease (16), (15). The proportion of patients diagnosed with M1 disease at initial presentation, according to the South Australian Hospital Registry, is 31% (5). By excluding the data on unstaged patients, patients with metastatic disease represent 27%, which is similar to the South Australian figure. Operability rate Not all patients with M0 disease will be fit enough for a radical nephrectomy. No direct accurate data on performance status or incidence of co-morbidities in renal cancer were available. According to the South Australian Hospital Registry data, the proportion of M0 patients not undergoing any surgical therapy is 2%. It is presumed this is due mainly to poor performance status or poor life expectancy from co-morbidities. An occasional patient may receive palliative radiotherapy but this number would be very small and an estimate of this proportion is unlikely to have an impact on the overall radiotherapy utilisation estimate. Positive margins post-nephrectomy the issue of whether radiotherapy is recommended is contentious. Radiotherapy has no established role as primary definitive therapy of early renal cancer or as an adjuvant to surgery. Two randomised trials have failed to show any benefit for postoperative radiotherapy (18) (19). Campbell and Novick report that of 7 studies identified, 24/668 (4%) developed an isolated local recurrence. As this was the largest study in the literature this value of 4% was used in the utilisation tree. To address this controversy sensitivity analysis was performed whereby the proportion of local recurrences to receive radiation was set at 4% as this correlated with the guideline recommendation and in the sensitivity analysis the alternative of no patients receiving radiation was considered. The median follow up was 66 months (5-179 months) and patients were followed prospectively using a pre-determined follow up protocol. They found that in 54 patients treated with nephrectomy for M0 renal cell carcinoma, 19 patients (35%) developed distant recurrence. The best incidence data for development of metastases in terms of lengthy duration of follow up, prospective design and large sample size is Lgungberg et al. Sensitivity analysis was performed to assess the impact that the variability of this data (23-58%) has on the overall estimate. Proportion of patients with M1 disease who have metastases to bone Radiotherapy is recommended for symptom control in patients with symptomatic bone metastases. However, specific examination of the palliation of symptoms for bone metastases for renal cancer show benefit for >50% of patients (27). However, no data are presented as to the proportion of M1 patients who subsequently develop bone metastases prior to death and therefore this may under-represent the final rate. In the tree, it has been assumed all patients with metastatic bone disease will be symptomatic at some point of their remaining life to warrant consideration of radiotherapy. Proportion of patients with M1 disease who have metastases to the brain Radiotherapy is recommended for symptom control in patients with brain metastases. Tumours such as renal cancers have previously been reported as being radioresistant. However, specific examination of the palliation of symptoms for brain metastases for renal cancer show benefit for >50% of patients (27). They reported that of 114 renal cancer patients studied, the cumulative incidence of brain metastases was 10% for all stages at diagnosis. No mean or median follow up time was reported but 101/106 (95%) of patients were deceased at the study cut-off date. However, sensitivity analysis was conducted to assess the impact that this variation in data had on the overall optimal radiotherapy utilisation rate. Randomised, controlled trials of adjuvant systemic therapy +/nephrectomy have revealed a survival benefit for nephrectomy in selected patients with good performance status and limited metastatic disease (15). Treatment options for patients with metastatic disease and symptomatic primary therefore include nephrectomy without radiation, palliative radiotherapy alone or radiation followed by nephrectomy in patients who fail to respond to radiotherapy. Sensitivity analysis was conducted to assess the impact of this treatment uncertainty on the overall radiotherapy utilisation estimate. The tree will use a value of 0 for patients with symptomatic primary who receive palliative radiotherapy. Proportion of patients with M1 disease who have symptomatic lymph node or skin metastases A study by Ljungberg et al. In terms of frequency of symptomatic primary in patients with metastatic disease, Ljungberg et al. In the entire group with metastatic disease, 34 (32%) required radiotherapy but no details were provided about whether this was to a symptomatic primary or to secondary disease. Follow up period was 6 months-17 years but no mean or median follow up time was reported. Expected value and sensitivity analysis the calculated overall rate of optimal radiotherapy utilisation in renal cancer was 28%. As renal cancer represents 3% of all cancers, this population of patients represents 0. There were two treatment branches where uncertainty of treatment recommendations existed. Therefore, sensitivity analysis was necessary to assess the impact of this uncertainty on the optimal radiotherapy utilisation rate. In addition, there were two data items (proportion of patients with metastatic disease who have brain involvement and proportion of patients who develop distant metastases post-nephrectomy), where the reported values varied significantly. The graph below shows that varying the proportions for each of these two values altered the renal cancer optimal utilisation rate from 25% to 35%. Tornado Diagram at Kidney Proportion of kidney cancer that develop distant metastases: 0. Th e incidence ofattributes used to define indications forradioth erapy K ey Populationor Attribute Proportionof Q ualityof R eferences N otes subpopulationof interest populationwith inform ation thisattribute A Allregistrycancers Bladdercancer 0. The bladder cancer treatment guidelines do not specifically recommend radiotherapy for the palliation of metastases from bladder cancer as the predominant focus of the guidelines is on the management of non-metastatic disease.

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Normal prolactin levels and resumption of menses should not be considered absolute proof of tumor response to treatment erectile dysfunction treatment food buy generic top avana on-line. Discontinuation of bromocriptine therapy after 2-3 years may be attempted because some adenomas undergo hemorrhagic necrosis and cease to function top erectile dysfunction pills buy generic top avana canada. Pituitary Disorders-Macroadenomas Macroadenomas are pituitary tumors that are larger than 1 cm in size erectile dysfunction caused by vascular disease generic top avana 80 mg on line. Bromocriptine is the best initial and potentially long-term treatment option erectile dysfunction lotion order top avana 80 mg with mastercard, but transsphenoidal surgery may be required erectile dysfunction 9 code top avana 80 mg for sale. Symptoms of macroadenoma enlargement include severe headaches erectile dysfunction future treatment discount top avana 80 mg fast delivery, visual field changes, and, rarely, diabetes insipidus and blindness. This may be performed earlier if new symptoms develop or if there is no improvement in previously noted symptoms. Normalized prolactin levels or resumption of menses should not be taken as absolute proof of tumor response to treatment. Macroadenomas treated with bromocriptine routinely show a decrease in prolactin levels and size; nearly one-half show a 50% reduction in size, and another one-fourth show a 33% reduction after six months of bromocriptine therapy. Because tumor regrowth occurs in over 60% of cases after discontinuation of bromocriptine therapy, long-term therapy is the rule. Because tumors may enlarge despite normalized prolactin values, a reevaluation of symptoms at regular intervals (6 months) is required. Surgical Intervention Tumors that are unresponsive to bromocriptine or that cause persistent visual field loss require surgical intervention. Some neurosurgeons have noted that a short 2-6 week course of preoperative bromocriptine increases the efficacy of surgery in patients with larger adenomas. Unfortunately, despite surgical resection, recurrence of hyperprolactinemia and tumor growth are not uncommon. Complications of surgery include cerebral carotid artery injury, diabetes insipidus, meningitis, nasal septal perforation, partial or panhypopituitarism, spinal fluid rhinorrhea, third nerve palsy, and recurrence. Metabolic Dysfunction Occasionally, patients with hypothyroidism exhibit hyperprolactinemia with remarkable pituitary enlargement due to thyrotroph hyperplasia. These patients respond to thyroid replacement with reduction in pituitary enlargement and normalization of prolactin levels. Prolactin levels are not normalized through hemodialysis but are normalized after transplantation. Drug-Induced Hyperprolactinemia Numerous drugs interfere with dopamine secretion (Table 25. The same principles utilized in the management of pituitary microadenomas or hyperplasia can be applied in these situations. If discontinuation of the drugs is feasible, resolution of hyperprolactinemia is uniformly prompt. Use of Estrogen in Hyperprolactinemia In rodents, rapid pituitary prolactin-secreting adenoma (prolactinoma) occurs with high-dose estrogen administration. However, even conditions associated with high estrogen levels, such as pregnancy, do not cause prolactinomas in humans. Studies and autopsy surveys indicate that estrogen administration is not associated with clinical, biochemical, or radiologic evidence of growth of pituitary microadenomas or the progression of idiopathic hyperprolactinemia to an adenoma status. For these reasons, estrogen replacement or oral contraceptive use for hypoestrogenic hyperprolactinemic patients secondary to microadenoma or hyperplasia is appropriate. Monitoring Pituitary Adenomas in Pregnancy Prolactin-secreting microadenomas rarely create complications during pregnancy. However, monitoring of patients with serial gross visual field examinations and fundoscopic examination is recommended. Because serum prolactin levels are elevated throughout pregnancy, prolactin measurements are of no value. Although not recommended, bromocriptine use during pregnancy in women with symptomatic (visual field defects, headaches) microadenoma enlargement has resulted in resolution of deficits and symptoms. Pregnant women with previous transsphenoidal surgery for microadenomas and/or macroadenomas may be additionally monitored with monthly Goldman perimetry visual field testing. Bromocriptine has been used on a temporary basis to resolve symptoms and visual field deficits in symptomatic macroadenoma patients to allow completion of pregnancy before initiation of definitive therapy. Breastfeeding is not contraindicated in the presence of microadenomas or macroadenomas. Incomplete: Incomplete expulsion, with some products of conception retained in uterus. Abruption placentae: Separation of the normally located placenta from its uterine attachment between the 20th week of pregnancy and the birth of the infant. Acromegaly: Over growth of the terminal parts of the skeletal system after epiphysial fusion, as a result of over production of growth hormone. Adenomyosis: Presence of endometrial tissue within myometrium as a result of direct extension. Adnexa: Uterine appendages, including the fallopian tubes, ovaries, and associated ligaments. Adrenal hyperplasia: Congenital or acquired increase in the number of cells of the adrenal cortex, occurring, bilaterally and resulting in excessive excretion of 17-ketosteroids with signs of virilization. Secondary: Absence of menses for three or more months occurring after the menarche. Amniocentesis: Aspiration of arriniotic fluid, usually transabdominally, for diagnostic or therapeutic purposes. Androgen Insensitivity: A syndrome of androgen insensitivity characterized by primary amenorrhea, a female phenotype, testes (abdominal or inguinal) instead of ovaries, the absence of a uterus, and a male genotype. Anemia, megaloblastic: Anemia with excessive megaloblasts in circulation, caused primarily by deficiency of folic acid, Vitamin B12 or both. Anorexia nervosa: Marked reduction in the intake of food, caused by psychogenic factors and leading to malnutrition and amenorrhea. Apgar score: the physical assessment of the newborn, usually at one and five minutes after birth. Arrhenoblastoma: Uncommon ovarian neoplasm associated with androgen production, causing amenorrhea, deferninization, and virilization. Atony, uterine: Loss of uterine muscular tonicity, which may result in failure of progress of labor or postpartum hemorrhage. The number of Barr bodies is one fewer than the number of X chromosomes in that cell. Basal body temperature: Temperature reading at rest used for detection of ovulation. Benign cystic teratoma: the most common germ-cell tumor, consisting of mature elements of all three 124 germ layers (often called dermoid cyst). Biphasic temperature curve: A graph showing basal body temperature rise in the luteal phase 0. Blood flow, uteroplacental: the circulation by which the fetus exchanges nutrients and wastproducts with the mother. Breakthrough bleeding: Nonorganic endometrial bleeding during the use of oral contraceptives. Irregular brownish patches of varying sizes appearing on the face during pregnancy and sometimes during the use of oral contraceptives. Choriocarcinorna: A malignant tumor composed of sheets of cellular and syncytial trophoblast. Chromophobe adenoma: Adenoma of the pituitary gland, consisting of cells that are neither acidophilic nor basophilic. Climacteric: the syndrome of endocrine, somatic, and psychic changes occurring at the termination of the reproductive period in woman, Clomiphene: Synthetic nonsteroidal compound that stimulates the maturation of follicles, resulting in ovulation, as a result of its antiestrogenic effect on the hypothalamus. Corpus luteum: Yellow endocrine structure formed in the ovary at the site of a ruptured ovarian follicle. Counseling, premarital: Advice given to a couple before marriage, dealing with medical, psychologic, sexual, and social matters. Cryptomenorrhea: A condition in which the menses occur without external bleeding, as with an imperforate hymen. Cul-de-sac: the pouch like cavity formed by a fold of peritoneum between the rectum and uterus. Dilutional anemia of pregnancy: Lower hematocrits are seen in pregnancy because the expansion of plasma volume is greater than the increase in red blood cell mass. Double set-up: the simultaneous availability of two sterile set-ups for both vaginal and abdominal operations. Endometriosis: the presence of endornetrial implants outside the normal intrauterine location. Estrogen, unopposed: Continuous and prolonged effect of estrogen on the endometrium resulting from a lack of progesterone. Ferning: the microscopic pattern of dried cervical mucus, resulting from the influence of estrogen. Fibrocystic disease (breast): Mammary disease characterized by fibrosis and formation of cysts in the fibrous stroma. Functional ovarian Cyst: A physiologic cyst arising from the graafian follicle or the corpus luteum. Galactorrhea: Spontaneous flow of breast milk in the absence of a recent pregnancy. Gonadal agenesis: Congenital malformation with absence of ovarian tissue or its presence only as a rudimentary streak. Gonadotropin: Human chorionic: A glycoprotein hormone that is produced by the synctiotrophoblast. Gravidity: the pregnant state, or the total number of pregnancies a woman has had including the current pregnancy. Hilus cell tumor: An uncommon ovarian tumor usually associated with deferninization or virilization. Hirsutism: the development in a woman of various degrees of hair growth of male type and distribution. Hot flashes: A vasomotor symptom characterized by transient hot sensations that involve chiefly the upper part of the thorax, neck and head. They are frequently followed by sweats and are associated with cessation or diminution in ovarian secretion of estrogen. Hydatidiform mole: A pathologic condition of pregnancy characterized by hydropic degeneration of the chorionic villi and variable degrees of trophoblastic proliferation. Hypercoagulable state of pregnancy: Increased predilection for pregnant women to have venous clotting episodes. Hyperplasia, endometrial: Adenomatous: Abnormal proliferation of the endometrium with a marked increase in the number of glands with increased and often abnormal mitotic activity. Hypoestrogenism: A condition of subnormal estrogen production with resultant atrophy or failure of development of estrogen-dependent tissues. Hypofibrinogenemia: A deficiency of circulating fibrinogen, usually below 100 mg percent. It may be seen in conditions such as abruptio placentae, amniotic fluid embolism, fetal death, and occasionally intraamniotic instillation of hypertonic saline, in which the fibrinogen is consumed by disseminated intravascular coagulation. Hysterectomy: Abdominal: Removal of the uterine corpus and cervix through an incision in the abdominal wall. Radical: Removal of corpus, cervix, and parametrium, with dissection of the ureters, usually combined with pelvic lymphadenectomy. Hysterosalpingography: Roentgenography of the uterus and tubes after injection of radiopaque contrast medium through cervix. Useful in ascertaining irregularities of the uterine cavity and patency of the fallopian tubes. Imperforate hymen: Failure of a lumen to develop at a point where the budding vagina arises from the urogenital sinus. Infertility: Inability to achieve pregnancy within a stipulated period of time, often considered to be one year. Intermenstrual bleeding: Uterine bleeding occurring between otherwise regular menstrual periods. Intervillous space: the in the placenta in which maternal blood bathes chorionic villi, thus allowing exchange of materials between the fetal and maternal circulations. Karyotype: A photographic reproduction of the chromosomes of a cell in metaphase arranged according to standard classification. Labor: the process of expulsion of the fetus from the uterus: Induced: Labor that is initiated artificially. Lactation: the production of milk through the actions of prolactin and other hormones on appropriately prepared breast tissue to create polyamines, casein, lactose and phospholipids. Lactogen, human placental (chorionic somatomammotropin): A polypeptide hormone produced by the synctiotrophoblast. It bears similarity to prolactin and somatropin from the pituitary and is intimately involved in carbohydrate metabolism of the mother and fetus. Laparoscopy: Transabdominal endoscopic examination of the peritoneal cavity and its contents after inducing pneumoperitoneum. Ligation, tubal: Surgical interruption of the continuity of the fallopian tubes for the purpose of permanent contraception. Membranes, premature rupture: Rupture of the amniotic membranes before the onset of labor. Menopause: Permanent cessation of the menses, naturally caused by ovarian failure. Menorrhagia (hypermenorrhea): Excessive or prolonged uterine bleeding in amount and duration of flow occurring at regular intervals.

The first clinical manifestation is testicular enlargement erectile dysfunction vitamins purchase cheap top avana line, which begins at a mean age of 11 causes of erectile dysfunction in 60s buy 80 mg top avana visa. Adult size and shape of the penis and scrotum is achieved between ages 12 and 17 with an average of about 15 years of age erectile dysfunction juicing cheap 80mg top avana amex, and pubic hair completes development at about the same time erectile dysfunction test yourself cheap 80mg top avana with mastercard. The testosterone effect on the vocal cords leads to the beginnings of voice changing at an average age of 13 buy erectile dysfunction drugs uk buy top avana 80 mg line, accompanied by the onset of spermatogenesis drugs for erectile dysfunction list top avana 80mg otc. The growth spurt continues with 45 % of the adult skeletal mass acquired between age 11 and age 18. Prior to puberty, males and females have similar muscle mass; but by the end of puberty, the average male has more muscle mass than the average female. The emotional responses to the changes in gonadal steroid are poorly understood, although all families and societies describe a marked change in pubertal children with respect to their relationships with their parents, peers and members of the opposite gender. Errors in Puberty (Delayed Puberty) Delayed puberty may be due to dysfunction of the hypothalamic/pituitary axis, end organ failure, or may be idiopathic. Constitutional delay of puberty may be due to chronic severe medical illness, weight loss or malnourishment, or physical stress (including chronic strenuous exercise). Adrenarche also still occurs (except in those children with pituitary and subsequent adrenal failure), but development of secondary sex characteristics does not follow. An evaluation of delayed puberty should be evaluated in girls who have no evidence of breast development by age 14 and in boys who have no evidence of genital growth by age 15. The Normal Menstrual Cycle Overview 13 One can analyze the menstrual cycle from many different points of view. The lay person is primarily aware of episodic uterine bleeding, the more or less regular interval between the bleeding episodes, and the interruption of the cycles by pregnancy. The hypothalamus and the pituitary, however, orchestrate a month-long interaction of the hypothalamic-releasing factors, pituitary gonadotropins, and steroid hormones. In the ovary, the morphologic and endocrine events of dominant follicle maturation and ovulation contrast sharply with the more sedate background of relentless early follicle development and subsequent atresia (only one follicle ovulates out of every 999 which initiate development). Meanwhile, the endometrium sees and responds to the cyclic and sequential appearances of estradiol and progesterone. The biochemist measures the concentrations of the relevant hormones in plasma throughout the cycle and wonders how these circulating hormones reflect or cause the key events in the menstrual cycle. Thus, the view that a person, or an organ, has of the menstrual cycle is highly relative to the position from which it is observed. Interaction of Hypothalamus, Pituitary, and Ovary Circulating concentrations of sex steroids and gonadotropins throughout the menstrual cycle are depicted in Figure 1. This process of recruiting a cohort of follicles from among which one will typically become dominant takes place by about the fifth day of the average menstrual cycle. More intense gonadotropin stimulation before this time in the cycle usually leads to multiple follicle maturations such as the use of gonadotropins for the treatment of infertility and in-vitro fertilization. The explanation of this phenomenon lies within the micro environment of the ovarian follicle. By the last few days before ovulation, virtually all of the ovarian estradiol secreted is produced by the ovary, and primarily by the follicle destined to ovulate. Long-term high concentrations of estrogens lead to pituitary suppression (as with oral contraceptive pills). After ovulation, the corpus luteum secretes progesterone at the rate of about 25 mg/day, yielding serum concentrations of the hormone typically between 5 and 25 ng/ml. This rate of steroid production by the early corpus luteum is roughly equal to the entire steroid output of both adrenal glands. In addition, the corpus luteum also secretes estradiol and 17-hydroxyprogesterone, an intermediate metabolite between progesterone and estrogen. After rupture and release of the ovum, capillaries penetrate the granulosa layer, enabling the delivery of circulating cholesterol, the necessary substrate for progesterone biosynthesis. Through sustained intra-ovarian processes of programmed cell death, the corpus luteum involutes 12 to 14 days after ovulation. At histologic analysis of endometrial tissue, glandular mitoses are typically seen. An increased risk of andenocarcinoma of the endometrium is associated with exposure over a period of many years to significant amounts of estrogen, either ingested orally, administered parenterally, or formed endogenously, typically by extraglandular aromatization of circulating androgens. This stimulation, without the naturally occurring progesterone from ovulation, or the administration of progestin, may lead to a hyperplastic endometrium and potentially, to cancer. Mitoses are almost never seen in endometrial specimens during the postovulatory phase of the menstrual cycle, and the incidence of adenocareinoma of the endometrium in premenopausal women with normal ovulatory function is nearly zero. This also explains the protective effect of oral contraceptives against endometrial cancer, as these medications always include a progestin. Falling progesterone in the secretary endometrium leads to the local production of prostaglandin by the decidua (the part of the endometrium which is sloughed each month). Prostaglandin causes vasospasm of the spiral arterioles, and subsequent ischemia and sloughing of the endometrium is what patients experience as a "periods. Beginning in the early thirties, there is epidemiologic evidence of a decline in fertility. The nature of these changes as perceived by an individual woman will be very different from person to person. The perimenopause is defined as that period around the menopause that is marked by unpredictable ovarian function and menstrual irregularity. Epidemiologic studies of normal women suggest that this is a period of about four years around the menopause although the variation from woman to woman is large. This time is marked by unpredictable ovulation and periods of both higher and lower than usual estrogen levels. Uterine bleeding may be more or less than "usual" in flow and the timing of uterine bleeding is also unpredictable. There are numerous physical and psychological phenomena attributed to this time of reproductive life (mood swings, vasomotor flushes, sleep disturbances, headaches, memory problems, decreased libido, urinary incontinence). It is not clear which are related to fluctuations of ovarian function, which are related to aging, and which are psycho-social responses to mid-life which may vary from person to person and culture to culture. Cigarette smoking, living at high altitude, exposure to some chemotherapeutic agents, and hysterectomy tend to slightly lower the age of menopause or final cessation of ovulation. Climacteric the climacteric is a term used for the transitional period including the perimenopause and the several years after the menopause. There are specific symptoms that some women may experience which are directly attributable to estrogen withdrawal (vasomotor flushes, urogenital atrophy), and there are some long-term aging and disease processes which are worsened by estrogen withdrawal (osteoporosis, coronary artery disease). There are number of other symptoms of aging which may be worsened by estrogen withdrawal (arthritis symptoms, cognitive function) but the evidence is not so clear. Until the last several hundred years, human life span was usually less than 50 years of age. The existence of a population of women who predictably lived well beyond the age of reproduction is new in human history. Through epidemiologic studies in aging women, many of whom took estrogen hormones for the treatment of vasomotor flushes, it was noted that long-term estrogen users had a decreased incidence of complications of osteoporosis and coronary artery disease. The health benefits and risks of estrogen therapy after menopause have been continuously evaluated over the past 35 years, and this therapy is now being subjected to prospective randomized trials. Recent prospective randomized trials of initiating continuous estrogen and progestin in older postmenopausal women did not show a health benefit with respect to protection against coronary artery disease, demonstrated a very small increase in the incidence of breast cancer and thromboembolic disease, and showed a decrease in osteoporotic fractures and colon cancer in women who took estrogen/progestin compared to placebo. Observations from women who had a uterus and took only estrogen after menopause revealed an increased risk of uterine cancer. Unopposed estrogen stimulation of the uterus, whether due to endogenous estrogens or estrogen therapy, causes endometrial hyperplasia and potentially adenocarcinoma of the uterus. The intermittent addition of progestational agents for 12 days each month causing endometrial shedding eliminates this increased risk. For older women, the thought of monthly periods is unattractive and is one of the major reasons for lack of compliance in postmenopausal hormone therapy. Another concern is the possibility of a small increase in the risk of breast cancer in long-term estrogen users. Exogenous estrogens for the menopause may also carry a very small increased risk of deep venous thrombosis and gallstone formation. The search for a physiologic event in men that would correlate to the menopause in women has been largely unsuccessful. Although the secretion of testosterone gradually declines with advanced age (the rate after 40 about 1% per year) is not enough to account for any decrease in libido or erectile function. Rather, the problems associated with loss of desire or erectile dysfunction are related to disease states or specific changes related to aging and not testosterone levels, themselves. These hormones are readily available at most super-markets and health food stores without a prescription. With an aging population and the possibility of a generation of physically incapacitated elderly men and women, the search for anabolic agents that will maintain musculoskeletal strength has become more intense. In numerous cross-cultural studies of men and women, there does not appear to be a well-defined entity called the "mid-life crisis. At the time of menopause women do have more concerns about health and aging than do men of similar age. Puberty is the coordinated sequence of biochemical and physiologic events including adrenarche and gonadarche that result in the growth spurt of adolescence, development of secondary sex characteristics, and reproductive capacity. Estrogen therapy significantly decreases hot flushes and vaginal atrophy and may substantially decrease the risk of postmenopausal osteoporotic fractures. Menopausal estrogen therapy for more that 5 years in women over 50 has been associated with a small increase in the detection of breast cancer. There is no clear rapid decline in gonadal function in men as there is in women, although there is a dramatic decline in adrenal androgens from their peak after puberty to middle age. Year Book Medical Publishers, Chicago, 1987 (a nice review of menopause) Speroff, Case, and Glass. To explain the essential and clinically relevant issues of spermatogenesis, spermiogenesis, and sperm maturation. To review the hypothalamic-pituitary-testicular hormonal axis and the role of hormones in spermatogenesis and male infertility. To describe the role of markers for the epididymis, seminal vesicles, and the prostate. To demonstrate through case studies common male fertility pathologies, diagnostic tools, and relevant therapies. Sertoli Cells Sertoli cells secrete proteins that are important to spermatogenesis including Androgen Binding Protein. Leydig Cells the Leydig cells produce the testicular steroids, lie between the seminiferous tubules, and assist in the transportation of steroids in the blood, lymph and seminiferous tubules. The yolk sac endoderm gives rise to primordial germ cells which give rise to more type A cells, some of which degenerate. Type A stem cells form additional type A cells or differentiate into type B spermatogonia cells during early puberty. Type B cells differentiate during late puberty and in the adult to form primary spermatocytes, secondary spermatocytes and spermatids. Regeneration of spermatogonia occurs through mitosis, while generation of the haploid spermatic occurs through meiosis. Spermatogenesis is the process by which spermatogonia reach the haploid, round spermatid stage. Spermiogenesis transforms early, round spermatids into late, differentiated spermatids, what we recognize as morphological normal sperm. Sperm are released into the lumen following spermiogenesis which involves a gradual loss of cytoplasmic remnants, passive diffusion, and contractile pressure. Testicular capsule contractions Sperm Maturation: Acquisition of sperm motility and fertilizing ability. Adrenergic innervation Ejaculation: Emission: Movement of semen into the urethra under sympathetic control (adrenergic receptors). Ejaculation Proper: Propulsion of semen out of urethra under parasympathetic control. Components of Semen: Epididymal Fluid: <5% of semen volume Seminal vesicles: 60-70% of semen volume. Qualitative fructose is useful for verifying presence and the presence of the vas deferens. Case Study #1 A 27 year old female presents with primary infertility (13 months w/o birth control). Cycles are approximately 30-32 days, with moderate cramping for 1-2 days of menses. Semen Analysis X2 Sexual Abstinance of >2 days Results of Semen Analysis: 6 6 6 6 Concentration: 1. Asthenospermia (azthenozoospermia): the production of an ejaculate in which less than 50% of spermatozoa are motile. Oligospermia (oligozoospermia): the production of an ejaculate containing less than 20 x 1C~ spermatozoa per milliliter of semen. Teratospermia (teratozoospermia) the production of an ejaculate in which more than 50% of spermatozoa are of abnormal shape. History: No significant medical history, no surgical hx, no relevant family history, no environmental exposures. Physical: Normal virilized, Normal size testicles, vas deferens palpable, no abnormalities noted.

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