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Therapy of endocrine disease: Steroidogenesis enzyme inhibitors in Cushing syndrome pregnancy 5 weeks ultrasound purchase fosamax 70mg with amex. In rare cases, radiation therapy can be used as primary therapy in patients who are not surgical candidates. Radiation therapy is effective in preventing tumor growth and controlling hypercortisolism in the majority of treated patients, but requires time to take effect, generally ranging between several months to a few years (Loeffler and Shih, 2011; Pashtan et al. In the interim, treated patients require medical therapy to control hypercortisolism (Tritos and Biller, 2014). To retrieve articles used in this review, computerized literature searches were conducted using the terms "Cushing disease" or "Cushing syndrome," "radiosurgery," "radiation therapy," "radiotherapy. Using conventional techniques, dose fractionation is required to minimize radiationinduced injury to off-target structures, including the optic chiasm, other cranial nerves, the cochlea and the brain. Other stereotactic techniques employ proton beams or helium beams, which deliver positively charged particles. Advanced methods in therapy planning and radiation beam shaping are required to achieve high tissue selectivity, which maximizes delivery of radiation to the intended target while minimizing exposure of healthy structures (Pashtan et al. In addition, the physical properties of charged particle beams (made up of protons or helium nuclei) are instrumental in achieving selective delivery of radiation to target tissues. Charged particle beams deliver most of their energy at a predetermined tissue depth, known as the "Bragg peak," which can be designed to deposit almost the entire particle energy within the target area with essentially zero exit dose, thus minimizing radiation exposure to healthy tissues (Pashtan et al. Stereotactic techniques optimize radiation delivery to the tumor (target tissue) while sparing healthy, radiosensitive structures, including the optic chiasm, other cranial nerves, the cochlea or the brain. This selectivity would be predicted to translate into a more favorable long-term safety profile. However, large studies of long duration are needed to establish this conjecture with certainty. Treatment Planning and Delivery the choice between treatment modalities used to deliver radiation therapy obviously depends on local equipment availability. Proton beam facilities are very expensive to set up and maintain, which has limited the use of this technique to a relatively small Encyclopedia of Endocrine Diseases, Second Edition, Volume 3 doi:10. Whenever possible, use of stereotactic techniques is advisable because of the potential advantages of these treatment modalities, as outlined above. These patients may still be treated with fractionated therapy, which is considered to be safer and may also be delivered via stereotactic techniques. During treatment planning, high resolution, cross-sectional imaging data are used to identify the target and establish a treatment plan by means of dedicated software. Patients who receive radiation therapy require medical therapy to control hypercortisolism until the salutary effects of radiation therapy occur (usually for a period ranging between several months to several years) (Tritos and Biller, 2014). However, published studies directly comparing two treatment modalities in a head to head manner are lacking. These findings have raised the possibility that concomitant medical therapy may blunt the effects of radiation therapy to the sella. On the basis of these data, it has been suggested that medical therapy be withdrawn for several weeks before administration of radiation therapy to the sella. However, allocation to concurrent medical therapy was not random in these studies. It is possible that patients who received medical therapy at the time radiation therapy was administered had more severe hypercortisolism at baseline. Thus, confounding by indication is another possible explanation for these observations. Recurrence of hypercortisolism may occur in a minority of patients who achieved endocrine remission after the administration of radiation therapy. Subsequently, biochemical recurrence developed in 15 patients at a median time interval of 38 months (Sheehan et al. Safety Patients who have received radiation therapy to the sella are at long-term (likely lifelong) risk of anterior hypopituitarism (Pashtan et al. In these patients, the normal pituitary gland is very close to the tumor target, thus imparting a substantial risk of radiation-induced damage to anterior pituitary function. Between 20% and 60% of patients who received radiation therapy developed one or more anterior pituitary hormone deficits at 5 years after treatment in different series (Estrada et al. Up to 85% of patients developed evidence of anterior hypopituitarism at 15 years after radiation therapy (Minniti et al. Proper treatment planning aimed at limiting radiation exposure to the radiosensitive chiasm and optic nerves can help minimize the risk of optic neuropathy. Conventional radiation therapy has been associated with a delayed risk of stroke, presumed to occur as a long-term consequence of irradiation of the major blood vessels in the circle of Willis and/or internal carotid arteries. Such cerebrovascular events have been reported in 4% of patients at 5 years after conventional fractionated radiation therapy, with cumulative risk rising further over time (Brada et al. With the advent of modern planning techniques, stereotactic approaches and proton beam radiation therapy, it is anticipated that the risks of these events will prove to be extremely low in the modern era. However, long-term studies of adequate size are needed in order to reliably estimate the risk of such delayed and infrequent potential adverse outcomes. Since there is a latency period after the administration of radiation therapy until hypercortisolism is controlled, medical treatment is required as a "bridge" intervention. All patients who received radiation therapy to the sella are at lifelong risk of anterior hypopituitarism and possibly of neurologic sequelae, and require long-term follow-up. Evaluation and Follow-Up of Patients With Cushing Disease After Pituitary Surgery References Brada, M. Treatment of pituitary adenomas by fractionated stereotactic radiotherapy: A prospective study of 110 patients. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). Stereotactic radiosurgery for hypersecreting pituitary tumors: Part of a multimodality approach. Heavy-charged-particle radiosurgery of the pituitary gland: Clinical results of 840 patients. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: Update after an additional 10 years. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. Stereotactic radiosurgery for pituitary adenomas: An intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. Bilateral Adrenalectomy for Cushing Disease Frederic Castinetti, Aix Marseille University, Marseille, France r 2019 Elsevier Inc. A chronic or acute increase in the cortisol level leads to a high number of clinical signs, hypertension, diabetes, osteoporosis, and depression. Bilateral adrenalectomy is now still considered as the ultimate therapeutic option in Cushing disease, probably because the "primum non nocere" paradigm is always considered by physicians who prefer to avoid adrenal insufficiency (Lacroix et al. This is why the majority of endocrinologists now prefer to use long-term medical treatments aimed at controlling cortisol hypersecretion: such treatments, as we shall discuss later, have their own drawbacks. The aim of this review is to clarify the potential roles of bilateral adrenalectomy in the management of Cushing disease. Since the first description of bilateral adrenalectomy in 1936 (Young, 1936), several technical advances have been done, the most important being laparoscopy about 25 years ago.

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Hirsutism is the most common sign womens health 4 week meal plan cheap 35 mg fosamax mastercard, ranging from 60% to 80% of the women (Bidet et al. Menstrual cycles irregularities has been reported in about 50% of the patients at diagnosis, are a reflection of these disturbances of the gonadotropic axis (Bidet et al. These disorders of the cycle are variable, ranging from primary (8%) or secondary (4%) amenorrhea to oligomenorrhea (46%) in a large cohort of 190 patients (Bidet et al. It is therefore important for any polycystic ovary syndrome chart to eliminate non classic 21-hydroxylase deficiency, according to the Rotterdam criteria. The overproduction of adrenal androgens appears to be the main disruptive factor of the gonadotropic axis. This may have a direct or indirect (via aromatization on estrogens) effect on ovary and gonadotrop axis function. This results in a loss of pulsatility of gonadotropin secretion, leading to anovulation or dysovulation. It has been also suggested that androgens may play a role in ovarian folliculogenesis via androgen receptors on granulosa cells. In addition, 21-hydroxylase deficiency can cause increased levels of progesterone. As it has been showed in women with classic 21-hydroxylase deficiency, increased adrenal progesterone production could disturb gonadotrop axis. The negative impact of elevated progesterone levels at the end of the follicular phase on embryo implantation rates has been shown in in vitro fertilization cycles. In addition, a "mini-pill" effect with inhibition of endometrial proliferation, a negative effect on cervical mucus and feedback on the gonadotropic axis may also occur. Similarly, in a recent French study on a cohort of 190 women, only 11% of women consulted for infertility, including 2. They described 187 pregnancies, 110 without and 77 with glucocorticoid treatment, occurred in 85 of the 95 women (90. The study of the cumulative incidence of pregnancies showed that 67% of women wishing to have conceived in the first 6 months and that 75. However when considering the 85 patients who conceived, the cumulative incidences of all pregnancies (83. It seems therefore possible that this treatment is likely to improve the fertility of these patients and the prognosis of their pregnancies. The high percentage of miscarriages may therefore reflect the poor quality of ovulation and/or the existence of an inadequate corpus luteum with its hormonal consequences on the uterine environment. That difference might be due to differences in the sample sizes of this study and the others. Dexamethasone should be avoided during pregnancy, and glucocorticoids such as hydrocortisone and prednisone, which are easily metabolized by placental 11 betahydroxysteroid dehydrogenase type 2, must be use (Speiser et al. However, in actual practice there are no biochemical markers and few clinical markers that should be followed in pregnancy, and doses are rarely adjusted. All studies suggest that using a physiological dose of glucocorticoids does not affect birth weight. There were also no differences in the rate of ectopic pregnancy, preterm birth, stillbirths, twins or multiple pregnancies (Moran et al. Enlargement of the genital tubercle continues to occur in late pregnancy without ongoing antenatal treatment, but it is generally responsive to postnatal treatment (Bachelot et al. Even though large-scale prospective studies are needed, this technique offers the possibility to only treat the affected female fetus. Rare adverse events have been reported in treated children, but no harmful effects have been documented that can be clearly attributed to this treatment (New et al. A recent large French retrospective study confirmed the absence of malformations and of growth restriction at birth (Tardy-Guidollet, 2015). But there has not been a confirmed association with major pregnancy complications such as hypertension, gestational diabetes, stillbirth or spontaneous abortions. These patients also had lower questionnaire scores in self-perceived scholastic competence and social anxiety. However, parents described these children as more sociable than controls, without significant difference in psychopathology, school performance, adaptive functioning or behavioral problems. The actual perspective of only treating affected girls will be a major improvement in the care of these at risk pregnancies. Its use to prevent or diminish the risk of virilization of the young girl has to be discussed taking account the potential long term use of such molecules on brain function or metabolism. Management of Endocrine Disease: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: Update on the management of adult patients and prenatal treatment. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pregnancy in women with nonclassic congenital adrenal hyperplasia: Time to conceive and outcome. Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Surgical outcomes and complications of reconstructive surgery in the female congenital adrenal hyperplasia patient: What every endocrinologist should know. Glossary Agonist Drug that has affinity for and stimulates physiological activity at cell receptors normally stimulated by naturally occurring substances. Antagonist Substance that tends to nullify the action of another as a drug that binds to a cell receptor without eliciting a biological response. Cryopreservation Maintenance of the viability of embryos or spermatozoa at extremely low temperatures. Diagnostic ultrasound Use of ultrasound to obtain images for medical diagnostic purposes, employing frequencies ranging from 1. Donor gamete/embryo Eggs, spermatozoa, or embryos contributed from one person (or couple) to assist in establishing pregnancy in another couple. Endometriosis Condition in which cells similar to those that form the inside of the uterus are found outside of the uterus; may cause internal bleeding, tissue inflammation, and subsequent scarring, pain, and infertility. Hysterosalpingography Insertion of a small tube into the cervix followed by injection of dye; the resulting X-ray is inspected for evidence of blockage or irregularity of the uterus or fallopian tubes. Laparoscopy Inserted through a small incision made just under the navel; looking through the scope, one can examine the ovaries, fallopian tubes, uterus, and other internal structures. Meiosis Consists of two cell divisions that result in four cells, each of which contains half of the number of chromosomes found in somatic cells. Surrogate pregnancy Purposely established pregnancy in which the woman who bears the pregnancy does not intend to raise the child. Unexplained infertility Diagnosis of exclusion when the standard investigation of both the female and male partners has ruled out other infertility diagnoses. In brief, oocyte retrieval (usually after controlled ovarian stimulation) and sperm collection, both required for the fertilization of oocytes outside the human body, are followed by the in vitro culture of embryos obtained under proper conditions. The whole process culminates into the transfer of selected embryos in the uterus to start a pregnancy. Because there was limited technology for observing events at a cellular level, study of mammalian fertilization did not progress further until after 1930 when Pincus began to study rabbit eggs and sperm under the binocular microscope. In 1944, Rock and Menkin reported in vitro fertilization of a human egg but did not intend to use the resulting embryo in an attempt to start a pregnancy. In 1967, Edwards and Steptoe began work on a technique for harvesting and fertilizing human eggs in vitro with the intention of treating infertile couples. Edwards reasoned that he could "simply pluck the egg from the ovary and fertilize it in the laboratory. Then, on July 25, 1978, Louise Joy Brown was born by caesarian section at Oldham General Hospital in England. Her birth was the first to demonstrate that conception in the laboratory could result in the birth of a normal baby.

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Special attention should be paid to patients with postoperative eucortisolism women's health center bakersfield proven fosamax 70mg, although this does not inevitably predict a recurrence. A baseline or stimulated concentration of 450 nmol/L or higher in modern assays almost rules out the risk of acute adrenal insufficiency and authorizes the cessation of hydrocortisone replacement. However, the variety of test protocols and markers used, the limited number of patients involved in most studies, and the lack of prospective comparative protocols hamper attempts to define an optimal management strategy. Clinical follow-up is mandatory, as some comorbidities may persist despite biochemical remission or even cure (Ragnarsson and Johannsson, 2013). The clinician should be aware that some comorbidities may take several months or years to resolve (Sippel et al. The spontaneous clinical course of recurrences following transient remission is poorly documented in the literature. Obviously, it is very important for the clinician to note his or her precise findings. Given the multiple clinical symptoms of Cushing syndrome, the development of a pertinent clinical score would be highly useful. Some patients who are exquisitely sensitive to glucocorticoids may experience early recurrence of a particular symptom such as hypertension or hyperglycemia. Elsewhere, some patients are intimately persuaded that their disease has recurred, based on psychological perception of their state during the phase of hypercortisolism. Stimulation testing has also been proposed to diagnose recurrences at an early stage. These results suggest that negative tests predict long-term remission more reliably than positive tests detect early recurrence. The limited number of patients studied and the relatively short follow-up hamper definitive conclusions on the usefulness of these investigations, which cannot currently be recommended for general use. Individualized follow-up is still difficult to define, owing to problems in accurately stratifying patients at a low versus a high risk of recurrence. In the opinion of the author, surgery in an expert center, followed by a very low early postoperative cortisol level and prolonged corticotropic insufficiency would favor a less rigorous (albeit long-term) follow-up schedule with yearly examinations, while more stringent follow-up (every 6 months) would be preferable for other patients. The predictive role of dynamic testing such as the desmopressin test deserves further prospective and comparative studies in large cohorts with lengthy follow-up. Long-term remission and recurrence rates in Cushing disease: Predictive factors in a single-centre study. Accuracy of late-night salivary cortisol in evaluating postoperative remission and recurrence in Cushing disease. Outcomes of therapy for Cushing disease due to adrenocorticotropin-secreting pituitary macroadenomas. Factors influencing the immediate and late outcome of Cushing disease treated by transsphenoidal surgery: A retrospective study by the European Cushing Disease Survey Group. Increased long-term remission after adequate medical cortisol suppression therapy as presurgical treatment in Cushing disease. Sequential hormonal changes in 21 patients with recurrent Cushing disease after successful pituitary surgery. Midnight salivary cortisol determination for assessing the outcome of transsphenoidal surgery in Cushing disease. Postsurgical recurrent Cushing disease: Clinical benefit of early intervention in patients with normal urinary free cortisol. Outcome of transsphenoidal surgery for Cushing disease: A single-center experience over 32 years. Mortality in patients with Cushing disease more than 10 years after remission: A multicentre, multinational, retrospective cohort study. Evaluation of Cushing disease remission after transsphenoidal surgery based on early serum cortisol dynamics. Accuracy of repeated measurements of late-night salivary cortisol to screen for early-stage recurrence of Cushing disease following pituitary surgery. Long-term remission and recurrence rates after first and second transsphenoidal surgery for Cushing disease: Care reality in the Munich Metropolitan Region. Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing syndrome. The complete normalization of the adrenocortical function as the criterion of cure after transsphenoidal surgery for Cushing disease. The burden of Cushing disease: Clinical and health-related quality of life aspects. Transsphenoidal microsurgery for Cushing disease: Initial outcome and long-term results. Outcome of Cushing disease following transsphenoidal surgery in a single center over 20 years. Surgical outcomes in patients with Cushing disease: the Cleveland clinic experience. Outcomes of primary transsphenoidal surgery in Cushing disease: Experience of a tertiary center. Predictors of mortality and long-term outcomes in treated Cushing disease: A study of 346 patients. Postoperative follow-up of Cushing disease using cortisol, desmopressin and coupled dexamethasone-desmopressin tests: A headto-head comparison. Persistent adrenocorticotropin response to desmopressin in the early postoperative period predicts recurrence of Cushing disease. Therapy of endocrine disease: Outcomes in patients with Cushing disease undergoing transsphenoidal surgery: Systematic review assessing criteria used to define remission and recurrence. Cushing syndrome: A structured short- and long-term management plan for patients in remission. Role for postoperative cortisol response to desmopressin in predicting the risk for recurrent Cushing disease. Incidence of venous thromboembolism in patients with Cushing syndrome: A multicenter cohort study. Evaluation and Follow-Up of Patients With Cushing Disease After Pituitary Surgery 231 Valassi, E. The desmopressin test predicts better than basal cortisol the long-term surgical outcome of Cushing disease. Endoscopic transsphenoidal pituitary surgery: A good and safe primary treatment option for Cushing disease, even in case of macroadenomas or invasive adenomas. Undetectable postoperative cortisol does not always predict long-term remission in Cushing disease: A single centre audit. Medical Therapy of Hypercortisolism Richard A Feelders, Erasmus Medical Center, Rotterdam, the Netherlands r 2019 Elsevier Inc. This chronic state of hypercortisolism results in multisystem morbidity and an increased mortality (Dekkers et al. This involves most frequently a benign unilateral adrenal adenoma and more rarely bilateral micro- or macronodular adrenal hyperplasia or a cortisol producing adrenal carcinoma (Lacroix et al. However, other treatment modalities including medical therapy, radiotherapy and bilateral adrenalectomy are necessary when surgery is not successful or not indicated in case of a high surgical risk or metastatic disease (Nieman et al. Adrenal Blocking Drugs Adrenal blocking drugs interfere with steroidogenic enzymes at different steps in the pathway of adrenal steroid hormone production. Ketoconazole suppresses many steroidogenic enzymes whereas metyrapone mainly inhibits the last step in cortisol synthesis by targeting 11-b-hydroxylase. Main side effects of ketoconazole are gastrointestinal complaints, hepatotoxicity and male hypogonadism, whereas metyrapone can cause gastro- 232 Encyclopedia of Endocrine Diseases, Second Edition, Volume 3 doi:10. Mitotane also inhibits multiple steroidogenic enzymes and has adrenolytic effects. For these properties it is mainly used for the treatment of adrenal carcinoma, aiming to suppress both steroid hormone production and cell growth (Baudry et al. Etomidate is an anesthetic drug that potently inhibits 11-b-hydroxylase and can only be administrated in an intensive care setting. Osilodrostat was generally well tolerated, main side effects were gastrointestinal complaints, hirsutism and hypocortisolism. Efficacy and safety of osilodrostat are currently evaluated in large multicenter trials.

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Adverse consequences of glucocorticoid medication: Psychological menopause jokes humor discount fosamax 35 mg visa, cognitive, and behavioral effects. Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Effects of glucose infusion on neuroendocrine and cognitive parameters in Addison disease. A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation. Corticosterone infused intracerebroventricularly inhibits energy storage and stimulates the hypothalamo-pituitary axis in adrenalectomized rats drinking sucrose. Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Elevated basal trough levels of corticosterone suppress hippocampal 5-hydroxytryptamine(1A) receptor expression in adrenally intact rats: Implication for the pathogenesis of depression. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. The associations among hippocampal volume, cortisol reactivity, and memory performance in healthy young men. Chronic unpredictable stress alters gene expression in rat single dentate granule cells. Stress responsiveness varies over the ultradian glucocorticoid cycle in a brain-region-specific manner. Disrupted corticosterone pulsatile patterns attenuate responsiveness to glucocorticoid signaling in rat brain. Disconnection and reconnection: the morphological basis of (mal)adaptation to stress. Psychological morbidity and impaired quality of life in patients with stable treatment for primary adrenal insufficiency: Cross-sectional study and review of the literature. Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. The effects of two different doses of hydrocortisone on cognition in patients with secondary adrenal insufficiency-Results from a randomized controlled trial. Glossary Autonomic nervous system A network of nerves that carry information from the central nervous system (brain and spinal cord) to nearly all internal organ systems; this nerve system can operate with minimal, if any, conscious effort and functions to maintain internal homeostasis. Cardiac output the volume of blood pumped by the left ventricle of the heart in 1 min; cardiac output is a measure of the pumping action of the heart. Cardiovascular system the organ system that includes the heart and all of the blood vessels-arteries, veins, and capillaries; it serves to supply all parts of the body with nutrients and to transport waste products for elimination. Diastolic pressure the minimum arterial blood pressure measured in large arteries during the rest phase (termed diastole) of the heart; this pressure, measured in millimeters of mercury (mmHg), is largely determined by the rate of outflow of blood from the arterial vascular compartment into the capillaries. Neurotransmitters and neurohormones Chemicals made by and stored in nerve cells that, on release by a process termed exocytosis, carry information from one nerve cell to another or from a nerve cell to a target cell. Systolic pressure the maximum arterial blood pressure (mmHg) measured in large arteries during contraction of the left ventricle and ejection of blood into the arterial compartment; this pressure is determined by the contractile functions of the left ventricle of the heart and the arterioles and compliance of the large arteries. Total systemic vascular resistance the resistance of the arterial compartment to the flow of blood being pumped by the left ventricle; the resistance comes from the state of contraction of vascular smooth muscle cells located in the terminal arterioles. Blood Pressure: Definition, Physiological Importance, and Characterization Definition Blood pressure is simply the pressure of the liquid within blood vessels. This article focuses on excessive blood pressure within the arterial blood vessel network, or arterial compartment, that is, the network of blood vessels that carry blood away from the left ventricle of the heart toward all tissues except the lungs, which receives blood from the right ventricle. Evolution has matched complex multicellular organisms with comparably complex circulatory systems. In mammals, blood, containing both cells and dissolved materials, circulates continuously through an extensive closed network of tubes (blood vessels). This vascular system actually consists of three separate but connected sections, or compartments: arterial (arteries), capillary, and venous (veins). The arterial compartment carries blood away from the heart, beginning with the aorta, which branches to the carotid arteries (subserving the head and brain) and to the descending aorta, which extends in an ever-branching manner to all other organ systems and tissues. The arterial system is a high-pressure circuit that allows all organ systems an equitable portion of the arterial Change History: February 2018. Jaworski, Hypertension, Overview, In Encyclopedia of Endocrine Diseases, edited by Luciano Martini, Elsevier, New York, 2004, Pages 577-588. Large arteries leaving the heart (termed conduit arteries) receive the full pressure and flow of the pulse of blood pumped (or ejected) from the left ventricle with each contraction of the heart. Conduit arteries serve as "feeder vessels" to an increasing number of smaller arterial vessels ultimately connecting with the capillary compartment within organ systems. The capillaries are the simplest blood vessels designed to facilitate exchange of nutrients and cellular waste between tissues and blood. Arterial pressure is highest in conduit vessels (aorta and carotid) and declines steadily as the arterial vessels become smaller with the lowest arterial pressure at the junction with the capillary network. Conduit arteries also serve to dampen the large "pressure pulse" generated by contraction of the left ventricle, and function to smooth out the pressure wave that spreads from the heart to the smallest blood vessels. One way this dampening and smoothing is accomplished is through the elasticity of the conduit vessel wall. This elasticity allows "capture" of a portion of the energy of the pulse of blood ejected by the heart into the arterial compartment. As the pressure wave progresses away from the heart, the conduit arterial walls relax and return the energy to the blood, supporting the arterial pressure while the heart is not contracting. This process is like the rebound of a stretched rubber band of a slingshot that exerts a force on the object being propelled (here blood), a process termed the "windkessel effect. When conduit arteries lose their elasticity, systolic hypertension, a disorder common in the elderly, may result. Arterial blood vessels are complex consisting of multiple cell types and several discrete layers. In immediate contact with blood is a single cell-thick lining of endothelial cells with underlying associated connective tissue proteins. Arterial endothelial cells serve many functions, including local release of chemicals that may relax or contract the vessel wall and regulation of hemostasis and clot formation. The intima is very important with many major functions including the following: (1) reduce viscosity and turbulence of flowing blood; (2) provide a source of chemicals that regulate thrombosis or clot formation; and (3) release chemical mediators that affect the state of contraction or relaxation of underlying smooth muscle cells. The middle layer of the arterial vessel wall is termed the "media" and consists primarily of multiple layers of contractile smooth muscle cells that can directly and indirectly affect local arterial pressure or vessel compliance. At the junction of the smallest arteries (arterioles) with the capillary compartment, the smooth muscle cells provide "resistance elements" that determine the rate of flow of blood out of the arterial compartment into the capillary network. Large conduit arterial blood vessels also contain a microvascular blood network within the adventitia that serves to insure all cells within the adventitia get perfused with oxygenated blood. Chronic hypertension results in cellular and functional changes within all three layers of arterial blood vessels and constitutes part of the hypertension syndrome. The capillary network constitutes the smallest blood vessels in all three compartments of the vascular system. These vessels consist of only a single-cell layer of endothelial cells with associated connective tissue proteins, and no media or adventitia. This structure permits rapid diffusion of materials, in both directions, between the blood within the vessel and fluids in the adjoining tissue. This vascular compartment is primarily a circuit for material and cellular exchange between the blood and tissues of the organ system. For this reason, it has significant importance in maintaining the amount of fluid outside of the vascular compartments and in tissues. An imbalance in fluid exchange, due to altered control of fluid dynamics between the arterial and venous compartments, contributes to tissue fluid retention in individuals with compromised heart function as well as in uncontrolled hypertension. Although antihypertensive drugs are not designed to work directly on the capillaries, many of these drugs do affect capillary functioning indirectly through improved fluid dynamics and enhanced elimination of retained fluids within tissues.

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Preoperative normalization of cortisol levels in Cushing disease after medical treatment: Consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamineagonists womens health obgyn 35 mg fosamax fast delivery. Expression and function of sonic hedgehog pathway components in pituitary adenomas: Evidence for a direct role in hormone secretion and cell proliferation. G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas. Pituitary-directed leukemia inhibitory factor transgene causes Cushing syndrome: Neuro-immuneendocrine modulation of pituitary development. This leads to a constellation of symptoms including weight gain with centripetal fat distribution, hypertension, irritability, excess hair growth, irregular menses, decreased glucose tolerance, impaired immunity, osteoporosis, and increased risk of cardiac events (Boscaro and Arnaldi, 2009; Raff, 2015; Lonser et al. The disease is typically diagnosed around 3 years after the onset of illness (Zilio et al. The disease is more common in women, with studies showing three to six times the prevalence compared to men (Lonser et al. The excess cortisol leads to central adiposity and fat deposits in face, supraclavicular, and posterior cervical spine regions, hyperglycemia, frequent ecchymosis, dark striae, excess sweating, proximal muscle weakness, edema, hypokalemia, thromboembolic events, psychiatric disorders like depression with cognitive impairment, and atypical infections. Of these symptoms, hypertension and abnormal glucose metabolism are the major predictors of morbidity and mortality in untreated disease. Established clinical guidelines recommend confirming excess endogenous cortisol by at least two of these screening tests (Nieman et al. When visible, the vast majority (90%) of pituitary corticotroph tumors are microadenomas. It should be noted, however, that incidental sellar hypodensities of small size (o10 mm) are present in approximately 10% of individuals in the general population. Confirmation of hypercortisolemia at the time of the procedure is a prerequisite for accurate testing (Giraldi et al. While this test is considered the gold standard for distinguishing between pituitary and ectopic sources, it requires considerable expertise to be performed safely and reliably. In rare cases it has been associated with thrombotic and neurologic complications. Anomalous venous drainage or incorrect sampling can limit the diagnostic performance of this test, thus, it is imperative that both the venous anatomy and accurate catheter positioning in the inferior petrosal sinuses be verified before and after specimen collection to ensure appropriate sampling. Remission rates range from 65% to greater than 90%, with higher rates of remission achieved by more experienced neurosurgeons (Valassi et al. Surgical options include microscopic approaches via either sublabial or endonasal exposure, as well as the endonasal endoscopic approach. The endonasal approach has become the more common of the microscopic approaches because of the decreased incisional morbidity, although some centers utilize the sublabial approach. Recurrences may be treated with repeat transsphenoidal surgery, as well as radiosurgery or radiation therapy with interim medical therapy until radiation therapy takes effect. Refractory cases requiring urgent remission may be considered for bilateral adrenalectomy. Microscopic the microscopic, compared to the endoscopic approach, offers the advantage of a binocular stereoscopic view with superior optics. After induction of general anesthesia, the patient is positioned supine with the head on a gel headrest or in 3-point fixation. In the endonasal approach, the posterior septal mucosa is infiltrated with local anesthetic containing epinephrine, and incised opposite the middle turbinate. The mucosa is lifted with a periosteal elevator, and the posterior septum fractured. A self-retaining nasal speculum provides retraction as the anterior wall of the sphenoid sinus is drilled to provide sufficient room for later insertion and manipulation of appropriately sized curettes. A laser Doppler probe may be used to help identify the position of the cavernous carotid arteries, especially in cases of medially located cavernous sinuses. Tumor fragments are dissected free and delivered from the gland using an assortment of ring curettes. The surface of the pituitary gland is closely inspected for residual fragments of adenoma. The authors employ fat harvested from a separate abdominal incision, which is then covered with a piece of previously harvested septal bone, titanium mesh, or other synthetic plug. The nasal mucosal flap is reapproximated, and the nasal passage inspected before completion of the procedure. Endoscopic the endoscopic approach offers the advantage of a wider field of view and the capacity to inspect regions of the sella with angled fiber bundles. The goal of exposure is to achieve a sphenoidotomy that extends from floor to roof of the sphenoid sinus and laterally to bilateral superior turbinates. At this point, the approach to the pituitary gland and tumor resection is similar to the microscopic technique. During tumor dissection, the endoscope can be affixed to the operating table with an articulating arm or held by the assistant, allowing the surgeon to use conventional bimanual techniques. Recent improvements in endoscope technology have provided much clearer high-definition visualization, including 4K resolution. Larger macroadenomas may have worse outcomes, perhaps because larger tumors are more likely to be invasive (Meij et al. Tumor invasion Patients with presence of tumor invasion are less likely to achieve remission after transsphenoidal surgery (Rees et al. Invasion of the cavernous sinus and dura or suprasellar tumor extension results consistently in a higher incidence of persistent disease (Hammer et al. Remission is unlikely even in cases where tumor seems to be removed from the cavernous sinus given the likelihood of dural involvement (Lonser et al. Intraoperative identification of an adenoma is an important positive prognostic factor, and allows selective adenomectomy to be performed rather than a potentially more morbid procedure such as partial or total hypophysectomy (Hofmann et al. Intraoperative ultrasonography has been reported to increase intraoperative adenoma localization and yield higher remission rates (Watson et al. Tumor Pseudocapsule Adenomas may sometimes create a "pseudocapsule" of surrounding fibrous tissue and compressed gland that, when present, may be an aide to tumor dissection and successful removal. This technique yields excellent results in experienced hands, with initial remission of 96. Biochemical remission Several biochemical parameters have been proposed to define remission, although a perfect predictor of long-term remission has not yet been identified. One study found 97% sustained remission in patients with serum cortisol less than 5 mg/dL within the first two postoperative days, although follow-up was brief at 33 months (Acebes et al. Due to this variable timeframe of recurrence, the overall rate is difficult to determine because studies report differing lengths of follow-up. Recurrence continues to increase over time with long-term follow-up (Hammer et al. Undetectable postoperative cortisol does not exclude the chance of future recurrence, and in one study where postoperative cortisol predicted remission at 6 months, it was not related to long-term remission (Atkinson et al. Recurrence rates may be a function of tumor size, with macroadenomas recurring more frequently as a results of increased invasiveness (Swearingen et al. However, a small study showed excellent long-term remission rates in patients with macroadenomas, and several studies have shown no difference in recurrence rates based on size (Yap et al. Undetected dural invasion may contribute to unresected tumor tissue, and dural invasion increases with adenoma size, patient age, and male gender (Meij et al. Repeat surgery should therefore be considered an option for refractory cases when initially remission was not achieved (Shimon et al. Patients who are successfully surgically treated have improved long-term mortality risk, whereas those with persistent disease have increased mortality (Swearingen et al. Endocrine Postoperative adrenal insufficiency is an anticipated sequela after a successful corticotroph adenomectomy.

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A testosterone-secreting gonadotropin-responsive pure thecoma and polycystic ovarian disease books on women's health issues buy 35mg fosamax with visa. Leydig cell hyperplasia and Leydig cell tumor in postmenopausal women: Report of two cases. Efficacy of selective venous sampling to localize a small ovarian androgen-producing tumor. Sertoli-Leydig cell tumors of the ovary: A Taiwanese gynecologic oncology group study. Virilization Masculinization of the body including increased muscle mass and body hair, deepening of the voice, breast atrophy and clitoromegaly. There is clear evidence that regular physical activity has positive physical and mental health effects in both women and men. It is therefore worrying that the average physical activity level in the Western population has gradually declined. More and more people become physically inactive, that is, have sedentary employment and do not exercise in their spare time. At the same time, there has been a dramatic increase in the proportion of women who engage in sports at all levels in recent decades. The increase of female athletes is also reflected in Olympic sports with an increasing proportion of women as participants. In London 2012, the proportion was 44% and this was the first Olympics in which women competed in all sports in the program. The increase of women at the elite level shows a positive trend that can hopefully lead to increased physical activity for the entire population. However, we have also gained knowledge that sports women may be at greater risk of medical complications, including menstrual disorders, loss of bone mass, and musculoskeletal injury. Athletic Amenorrhea-Functional Hypothalamic Amenorrhea In the late 1970s, an increased prevalence of menstrual disorders in female athletes was first reported (Loucks and Horvath, 1985). This finding and subsequent investigations gave rise to the term "athletic amenorrhea," that is, loss of menstruation due to intense physical exercise. Athletic amenorrhea can be either primary (spontaneous menstruation has never occurred) or secondary (absence of menstruation for at least three consecutive months). In comparison, the prevalence of athletic amenorrhea has been reported to range from 6% to 69% depending on the type of sport, age, and definition (Nattiv et al. The sports with highest occurrence of athletic amenorrhea are those in which a lean body composition is regarded an advantage for physical performance, such as esthetic or endurance sports, for example, gymnastics and long-distance running. Leanness is also of critical importance for effective performance in events involving weight classes, for example, wrestling, boxing, and martial arts and gravity opposing events such as the high jump and pole vaulting. However, the frequency of menstrual disorders may be underestimated, since mild disorders with luteal phase defects and ovulatory disturbances also have been demonstrated in athletes and these disturbances often are asymptomatic and thereby not clinically detected (De Souza et al. High intensity training at an early age could affect pubertal development adversely, including a delay of growth and menarche (Warren, 1980; Abraham et al. Delayed puberty in girls is defined as no pubertal signs by age 13 and delayed menarche is defined as no menstruation by age 16. The incidence of delayed puberty differs between sport disciplines, but is particularly common in gymnasts and ballet dancers. Some studies suggest that a genetically dependent delay in pubertal development leads to a selection bias to some disciplines such as gymnastics due to desirable physique characteristics related to delayed puberty. However, a break from exercise due to for instance injury often results in a rapid catch-up in pubertal development, indicating that environmental factors also play a role. In the normal case, cortisol increases acutely in response to physical activity to mobilize energy such as glucose and then the levels normalize at rest. In female athletes, however, chronic elevation of cortisol has been associated with increased blood glucose levels, low body fat, and amenorrhea (Lindholm et al. This hormone, produced in adipocytes, is an independent regulator of metabolism and levels are positively associated with body fat mass. Leptin is furthermore an important link between nutritional status and reproductive capacity. There are also leptin receptors in the ovary suggesting a direct regulatory effect on estrogen production. Thyroid hormones are also considered as markers of energy balance and low levels of thyroxin (T4) and triiodothyronine (T3) are observed in female athletes with functional amenorrhea (Loucks et al. Low Energy Availability and Disordered Eating It is today understood that the most important cause for athletic amenorrhea is low energy availability due to failure to ingest adequate energy in relation to energy expenditure (Loucks et al. The intense physical training necessary for top athletic achievement requires a high-energy output that many athletes do not match with a corresponding caloric intake. Recent advances have therefore led to the understanding that many sportswomen are chronically energy deficient. The reasons for this common discrepancy between energy intake and output include the difficulties involved in eating and digesting large portions of food alongside a demanding training program, and poor knowledge about energy and nutritional requirements. Another problem for athletes is that biological feedback mechanisms for energy balance are unreliable. For example, appetite does not necessarily reflect the caloric deficit induced by an intense training session (Truswell, 2001). However, a more common cause of energy deficiency is a conscious pursuit of leanness (Hagmar et al. These include endurance sports such as long-distance running and cycling as well as sports that overcome gravity, such as high jump. A low body weight or body fat content is also often an advantage in sports that are divided into weight classes, such as wrestling, boxing, and martial arts, or in sports with esthetic considerations, such as gymnastics and figure skating. These sports are the same as those with the highest incidence of athletic amenorrhea. Eating Disorders Female athletes have an increased risk of developing eating disorders compared with nonathletes and male athletes (SundgotBorgen, 1993; Beals and Hill, 2006; Sundgot-Borgen and Torstveit, 2010). Besides optimizing body composition for performance, some female athletes are also under the pressure to attain an appealing appearance. This is particularly true for athletes in esthetic disciplines, such as gymnastics and figure skating, but is becoming increasingly important in many other disciplines, due to scrutinizing media coverage and the importance of sponsorship. Disordered eating in athletes may advance along a continuous scale ranging from a normal but often strictly controlled food intake to a disturbed eating behavior that meets the diagnostic criteria for any of the eating disorders, such as anorexia nervosa or bulimia nervosa. In comparison, the prevalence of clinical eating disorders in female athletes has been reported to be about 20% to 30% in adult female elite athletes, and as high as 70% in weight-class sports (Gibbs et al. However, it should be mentioned that most of these results are based on surveys and not on clinical interviews, and survey data usually yields higher numbers than the actual occurrence. Bone Mass Today it is well-known that long-term amenorrhea and estrogen deficiency are associated with loss of bone mass, particularly of trabecular bone such as the lumbar spine and pelvis (Lambrinoudaki and Papadimitriou, 2010). It was initially considered paradoxical that elite athletes could develop reduced bone mass (Warren, 1980; Drinkwater et al. Mechanisms of Bone Loss Estrogen is important for bone turnover and acts through specific receptors in bone tissue to prevent bone resorption. Consequently, estrogen deficiency is associated with bone loss due to increased bone resorption (Almeida et al. Thus, even though physical activity usually increases bone mass, the overall result from energy deficiency and a catabolic hormone balance is suppressed bone formation and increased bone resorption resulting in a net loss of bone mass.

Syndromes

• In this procedure, a tiny tube is inserted into the eardrum, keeping open a small hole that allows air to get in so fluids can drain more easily. Tympanostomy tube insertion is done under general anesthesia.
• Movement problems
• Do NOT assume that any allergy shots the person has already received will provide complete protection.
• Swollen lymph glands
• Gentle handling
• Oxalic acid

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As outlined above breast cancer day discount fosamax american express, it is important for other causes of hyperprolactinemia to be excluded before a diagnosis of prolactinoma is made. In prolactinoma the degree of hyperprolactinemia is usually commensurate with the size of the adenoma. A large pituitary mass with mild hyperprolactinemia is usually due to a nonfunctioning adenoma rather than a prolactinoma. In rare cases which are not responsive to dopamine agonist therapy the diagnosis of prolactinoma may be confirmed by surgical removal of the adenoma and immunohistological analysis showing adenoma with a predominance of cells which stain positively for prolactin. Clinical Case 8 A 23 year old woman presented with secondary amenorrhea for 6 months. She was treated with a dopamine agonist, the serum prolactin level returned to normal, and menstruation was restored, supporting the diagnosis of prolactin-secreting pituitary microadenoma (microprolactinoma). Summary the clinical approach to assessing a patient with a raised serum prolactin level requires consideration of the several different causes of hyperprolactinemia. In each situation a disturbance in reproductive function may indicate the effect of the hyperprolactinemia. Prolactinoma is a common and well recognized cause of reproductive disturbance and hyperprolactinemia; however, several other causes of hyperprolactinemia should be considered before a diagnosis of prolactinoma is made. The small low signal lesion within the pituitary gland is characteristic of a microprolactinoma. It should be noted that prolactin is also secreted by tissues other than the anterior pituitary gland, and that there are prolactin receptors in a wide variety of tissues outside the reproductive system. Several functions for prolactin other than in reproduction have been recognized, including actions in the immune system and in relation to angiogenesis. Furthermore, prolactin is found in almost all vertebrates, including fish and birds, where its physiological role is clearly quite different. It should be remembered that our understanding of prolactin is incomplete, and that further research may reveal additional effects of hyperprolactinemia not generally recognized in current clinical practice. Prolactinomas: Clinical Manifestations and Therapy Anna Scholz, University Hospital of Wales, Cardiff, United Kingdom Dafydd Aled Rees, University Hospital of Wales, Cardiff, United Kingdom and Cardiff University, Cardiff, United Kingdom r 2019 Elsevier Inc. Introduction Prolactinomas are the commonest type of pituitary tumor, accounting for 40% of all pituitary adenomas. Symptoms and signs may arise from hyperprolactinemia per se and/or from local mass effects. Microadenomas (o10 mm in diameter), which predominate in women, are much commoner than macroadenomas (410 mm in diameter), which have a more equal gender split. Local mass effects can cause symptoms in the latter, dependent on adenoma size and extension outside the sella. Clinical Manifestations Table 1 summarizes the commonest clinical findings on presentation. Galactorrhea Nonpuerperal galactorrhea describes any discharge of milk from the breasts, and may be spontaneous or expressible on stimulation. Lactation is considered inappropriate when it occurs outside pregnancy or if it persists for more than a year after completion of breast feeding. Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. In contrast, 75% of women will have hyperprolactinemia when galactorrhea coexists with oligo/amenorrhea. Female Reproductive Function Hyperprolactinemia affects reproductive function by a number of mechanisms. As a consequence of these effects, hyperprolactinemia shortens the luteal phase, such that most women become anovulatory, with consequent oligo/ amenorrhea and infertility. Menstrual disturbance was reported in 94% of 41400 patients undergoing transsphenoidal surgery for prolactinoma. This usually manifests as secondary oligo/amenorrhea although can present as primary amenorrhea if the adenoma develops prepubertally, at which age macro- lesions predominate. Many patients with hyperprolactinemia present with infertility, which is inevitable when gonadotropins are suppressed. Most patients in this context have amenorrhea and galactorrhea but a small proportion do not. Dopamine agonist therapy may still be helpful in restoring fertility in such circumstances. Reduced libido may also be apparent, and usually improves when prolactin levels are normalized. Testosterone concentrations, which are typically low or in the low-normal range, improve with correction of hyperprolactinemia provided there is no structural compromise of the pituitary gland. Reduced libido and erectile dysfunction are present in some 90% of patients with chronic hyperprolactinemia, although other hypogonadal symptoms such as reduced beard growth and loss of muscle strength are rare. Sperm count and function may be affected but this usually improves with restoration of normoprolactinemia. Bone Mineral Density Long-standing hypogonadism secondary to hyperprolactinemia can lead to osteoporosis in both men and women. Bone mass improves in both sexes with correction of hyperprolactinemia and restoration of eugonadism. Mass Effects As with any macroadenoma, macroprolactinomas may induce symptoms through local mass effects. Whilst delayed presentation may account for this in part, macroprolactinomas in men tend to be more invasive and resistant to dopamine agonist therapy, and display greater proliferative potential. Visual field defects may range from classical bitemporal hemianopia (which is not always symmetrical) to smaller quadrantic defects or scotomas. Invasive tumors causing bony destruction in the skull floor can also cause cranial nerve entrapment, in addition to compression of other base-of-skull structures. Exact definitions vary, but common criteria are a diameter of 44 cm with significant extrasellar extension and markedly raised prolactin levels. Massive extrasellar extension in such tumors can cause hydrocephalus and temporal lobe epilepsy. Moderate to severe headaches are most commonly reported by women with macroprolactinomas. Sudden onset of a severe headache, with or without visual compromise and reduced consciousness, should raise suspicion of pituitary apoplexy. This can rarely occur as the first presentation of a macroprolactinoma, but can also develop following initiation of dopamine agonist therapy. Local mass effects can cause hypopituitarism, either due to direct compression of anterior pituitary cells or as a result of hypothalamic/pituitary stalk compression. Rarely, clinical manifestations of prolactinomas can result from co-secretion of other hormones. Prolactinomas: Clinical Manifestations and Therapy Additional Features 321 Up to 5% of clinically diagnosed pituitary adenomas occur due to hereditary tumor syndromes. Therapy the goals of treatment are to restore gonadal and sexual function, to improve symptomatic well-being and, in macroprolactinomas, to reduce tumor size. Women seeking fertility with normal menses and mild hyperprolactinemia may also benefit from treatment. Treatment may not be necessary in women with regular cycles and nontroublesome galactorrhea nor in postmenopausal women with microprolactinomas and nontroublesome galactorrhea. Regular surveillance with monitoring of prolactin levels is nevertheless important as an indicator of potential tumor expansion. Medical Therapy Dopamine agonists are the primary therapy for patients with prolactinomas. Whilst all dopamine agonists are effective, pergolide and quinagolide are much less commonly used than cabergoline and bromocriptine. A number of studies have shown that cabergoline is more effective than bromocriptine in normalizing prolactin levels, restoring gonadal function and reducing tumor size, potentially due to a higher binding affinity for receptor binding sites. Cabergoline is also better tolerated and more convenient to administer; treatment adherence may therefore be better with cabergoline.

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A causative relationship between higher hydrocortisone dose and these adverse outcomes has not been demonstrated breast cancer decorations order 70 mg fosamax mastercard. While recommendations can be made regarding hydrocortisone doses, it will always be important to consider how individual variability in glucocorticoid sensitivity and metabolism may require titration of doses against symptoms of cortisol deficiency and excess, and serum cortisol concentrations. Despite these data, favoring lower compared to higher daily doses, the authors of a recent systematic review and metaanalysis found no evidence of benefit from low total daily doses of hydrocortisone (20 mg vs. They did, however, report improved QoL in patients treated using subcutaneous hydrocortisone infusions and modified release hydrocortisone. In a double blind, placebo controlled trial, a 10 mg dose of hydrocortisone taken 1 h before intensive exercise had no effect on exercise performance, metabolic or endocrine parameters or sense of well-being, although cortisol concentrations were double those recorded in healthy control subjects (Simunkova et al. Hydrocortisone therapy in childhood In pediatric practice, hydrocortisone and cortisone doses are always derived from measurements of body size, generally body surface area. Doses are titrated against clinical features of adrenal insufficiency or glucocorticoid excess as in adult practice, and monitoring growth and weight gain provides additional, important information. Prednisolone Treatment with prednisolone is recommended for adult patients in whom the symptoms of adrenal insufficiency cannot be treated adequately with hydrocortisone, and those in whom adherence to the three times a day, hydrocortisone treatment regimen is difficult. Another use for prednisolone could be in those who are unable to take their hydrocortisone tablet for a long period such as during prolonged fasting. Prednisolone is absorbed rapidly following oral administration and concentrations peak within the first hour (English et al. Like hydrocortisone, the plasma half-life of prednisolone is reported to show marked interindividual variability, even after intravenous administration, and ranges from 120 to 360 min (English et al. The longer half-life results in a smoother profile of glucocorticoid exposure, enabling once daily dosing. On the other hand the effect of hydrocortisone is faster with rapid redistribution of the receptor-response element on completing a glucocorticoid response (Stavreva et al. Recommended doses are either as a daily dose of 4 or 5 mg at 07:00 h or as a twice daily dose of 3 mg and 2 mg or 3 mg and 1 mg at 07:00 h and 14:00 h, respectively (Husebye et al. The growth suppressive effect has been reported to be 15-fold that of hydrocortisone (Punthakee et al. The spectrum of potencies of prednisolone on systems regulated by glucocorticoids suggest the determinants of the synthetic glucocorticoid activity are not simply dose related, but are regulated by differential effects on glucocorticoid target genes. Prednisolone is used rarely in childhood, as its high potency increases the risk of clinical features of glucocorticoid excess, in particular poor growth (Punthakee et al. It may be helpful in some adolescent patients, nearing completion of growth in whom adherence to a three times daily dosing regimen required for hydrocortisone is particularly difficult. A modified release formulation of prednisolone with a delayed release mechanism, Lodotra, has been produced as an attempt to try and provide more physiological replacement. By administering this drug before sleeping at 22:00 h patients with adrenal insufficiency showed a better quality of life with less complaints and fatigue when compared to taking prednisolone on waking, highlighting the importance of early morning glucocorticoid exposure (Langenheim et al. Randomized placebo controlled studies are necessary to confirm the benefits of this formulation in patients with adrenal insufficiency. Dexamethasone the use of dexamethasone as a cortisol replacement therapy is discouraged in both adult and pediatric practice. The plasma halflife is around 200 min and the biologic half-life varies between 36 and 54 h. The potency, estimated by antiinflammatory effect, is 30 times that of hydrocortisone though the antigrowth effect may be up to 80 times higher (Finkielstain et al. Dose titration is difficult because of the potency of dexamethasone, and the risk of Cushingoid side effects is high (Clayton et al. Although better control of androgens is achievable with dexamethasone and so the drug may be useful for a short period to improve fertility in women and reduce testicular adrenal rest tumor size in males it is associated with a high risk of metabolic complications such as insulin resistance (Han et al. Steroid Replacement in Adrenal Insufficiency Subcutaneous Hydrocortisone Infusion 179 the use of insulin pumps to administer hydrocortisone subcutaneously, offers the opportunity to reproduce the physiological, diurnal profile of cortisol. Infusion sets and cannula need to be re-sited every 3 days, and patients need to learn how to increase hydrocortisone infusion rates during periods of ill health. Despite considerable advances in pump technology, technical problems still occur frequently, and site infections are not uncommon (Ross et al. They may also be useful in patients with gastric side effects or fast metabolizers. Jersey) is a modified release hydrocortisone with an outer coating layer that provides an immediate release of the drug and an extended release core. Plenadren provides a more extended serum profile of cortisol compared to immediate release Hydrocortisone. In adults a single morning dose of Plenadren gives similar cortisol exposure to a thrice daily regime of immediate release hydrocortisone although Plenadren tends to provide higher levels of cortisol in the late morning and lower in the late evening than a conventional regime and overall has approximately 20% less bioavailability (Johannsson et al. Studies in adult patients reported promising results, with improvements in metabolic profiles, weight, and blood pressure (Quinkler et al. Chronocort aims to replace physiological cortisol levels by dosing at morning and night such that the night time dose provides release of hydrocortisone in the early hours of the morning providing a prewaking rise in cortisol levels and a cortisol profile similar to physiological cortisol levels (Whitaker et al. Management of Adrenal Crisis Adrenal crisis is a life threatening condition which requires immediate treatment. Patient education regarding possible precipitants, the need to increase glucocorticoid doses during periods of stress and prompt recognition of the early features of adrenal crisis is essential. Other common precipitants include flu like illnesses, and in children, respiratory tract infections. The introduction of new medications that alter glucocorticoid clearance (Table 2) may also precipitate adrenal crisis. The biochemical features of adrenal crisis include hyponatraemia and hyperkalaemia in patients with mineralocorticoid deficiency with a high urea. The treatment of adrenal crisis is based on expert opinion, and to date no clinical trials have been performed to determine the optimal glucocorticoid dosing regimen in either adults or children. Management of Intercurrent Illness and Surgical Stress Early management of intercurrent illness and surgical stress should avoid progression to acute adrenal crisis in most patients. The cortisol response to stress reflects the intensity, duration and nature of the stressor, and hydrocortisone doses titrated against the severity of the stress are recommended. While there is little doubt that severe stress requires additional glucocorticoid, the threshold at which doses should be increased is uncertain. An effect of general anesthesia on cortisol concentrations has been studied in children and adults. Approximately a quarter of children undergoing general anesthesia for elective imaging demonstrated a stress response (Hsu et al. A study of adult patients undergoing thyroidectomy or parathyroidectomy, described a cortisol stress response during reversal of anesthesia, endotrachial extubation, and the early recovery period, but not during the surgical procedure (Udelsman et al. Studies of the cortisol response to minor surgery, for example, inguinal hernia repair in adults (Chernow et al. During childhood febrile illnesses cortisol levels are reported to be three to five times higher than baseline levels, with the magnitude of change reflecting the severity of the illness (Nickels and Moore, 1989). Glucocorticoid dosing regimens draw on data reported in studies measuring cortisol secretion rates during surgery. In a review article published in 1994, data from seven studies were integrated (Salem et al. Recommended doses are higher than these, recognizing that there are currently no data to demonstrate that these doses have an adverse effect, or that lower doses are safe. The recommendations of the Endocrine Society, in collaboration with the European Society of Endocrinology and the American Society for Clinical Chemistry (Bornstein et al. Conclusion Patients with adrenal insufficiency have a higher mortality rate compared to the normal population and are at risk of multiple complications, including metabolic disturbances, a poor quality of life and adrenal crises. Conventional glucocorticoid replacement since development in mid-20th century has had a positive impact on the lives of these patients but remains inadequate. Oral modified release hydrocortisone formulations and subcutaneous hydrocortisone infusion pumps that mirror the physiological cortisol circadian rhythm are promising but long term studies assessing metabolic outcomes, quality of life and mortality are still awaited.

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Estrogen appears to increase bone mass by exerting anabolic as well as antiresorptive effects pregnancy genetic testing order 35 mg fosamax visa. However, the inherited states of impaired estrogen synthesis or action do not clearly reflect the role of estrogen in maintaining bone density in the mature adult skeleton. In particular, the decreased bioavailable E2 levels in elderly men appear to be a good predictor of age-related bone loss (Khosla et al. Estrogen alone was far more effective than testosterone alone in preventing an increase in bone resorption markers (Falahati-Nini et al. Estrogen and testosterone combined have positive synergistic effects on bone remodeling. Based on the data, it was estimated that estrogen is responsible for about 70% of the total effect of sex steroids on bone resorption, whereas testosterone (in the absence of conversion to estradiol) accounts for no more than 30% of the effect. Another study reported that when elderly men were treated with an aromatase inhibitor for 9 weeks, they had a significant increase in bone resorption markers and a decrease in bone formation markers when compared with baseline (Taxel et al. Therefore, a subset of elderly men with low bioavailable E2 are the most susceptible ones to age-related bone loss similar to the increased risk of bone loss seen in postmenopausal women. It was also shown that E2 deficiency primarily affected cortical bone due to increased cortical porosity but had minimal 754 Estrogen and the Male Table 3 Patient Effects of estrogen deficiency states on skeleton Age (years) 28 24 38 27 29 25 26. Estrogen deficiency is associated with propensity of developing insulin resistance (Table 5). The estrogen-resistant man had axillary acanthosis nigricans, a cutaneous marker of insulin resistance, in addition to elevated glycosylated hemoglobin. Similar features were observed in majority of men with aromatase deficiency: 13 of the adult men were overweight and nine had impaired glucose tolerance of varying degree. Most of the impairments resolved with estrogen replacement, with a notable exception of the estrogen-resistant man. Similar results were shown in healthy men with induced hypogonadism: a decrease in E2 through blocked aromatization lead to an increase in adipose tissue that was independent of T, while androgens were responsible for lean mass and other muscle parameters (Finkelstein et al. There is evidence to suggest that severe estrogen and testosterone ratio imbalance increases insulin resistance in estrogendeficient men, as well as in rodent models (Mauvais-Jarvis, 2011). Aromatase deficient men are not homogenous, however, as in a patient, described by Chen et al. Data on estrogen effects on insulin sensitivity remains inconsistent in studies done in humans of both sexes, as well as animal models. It seems that favorable estrogen effect depends on a tight physiological concentration of E2. Estrogen can also cause arterial vasodilation through nongenomic pathway by activating endothelial cell nitric oxide synthase (Paper et al. Atherosclerosis Endothelial dysfunction is an early contributor to developing atherosclerosis. Low-dose estrogen replacement improved endothelial function and diffuse atherosclerosis in men with aromatase deficiency (Carani et al. Moreover, men who were treated with aromatase inhibitors due to prostate cancer, showed reversible endothelial dysfunction (Mendelsohn and Rosano, 2003; Lew et al. Ischaemia Estrogen replacement therapy has been attributed to increased risk of myocardial infarction and death in men (Coronary Drug Project Research Group, 1974). However, recent data has shown potentially beneficial estrogen effects in cellular ischemia models, possibly through reduction in intracellular calcium and sodium during metabolic inhibition, as demonstrated in male mice cardiac myocytes (Sugishita et al. Estrogen concentration in the stroma increases with age with contributions from peripheral sources and from aromatization of androgen within the stroma. Therefore, estrogen can increase epithelial proliferation indirectly by enhancing androgen action. Alternatively, estrogen may exert antiandrogen effects within the tumor cells, or it may be directly inhibitory to the tumor cells. Epidemiological studies demonstrate geographical differences in incidence rates of prostate cancer, with a 15-fold greater incidence in the United States than in Japan and a 60-fold greater incidence in the United States than in Shanghai, China (Hsing et al. The geographical differences have been attributed to dietary factors such as soy (phytoestrogens), which may be protective against the development of prostate cancer, in addition to genetic factors (Zhang et al. Estrogen and Central Nervous System A number of studies have shown estrogen to have neuroprotective, antioxidative, and antiinflammatory effects in the brain (Brann et al. Estrogens are involved in various cognitive functions such as learning and memory; effect on physiological and behavioral endpoints including social behavior, cognition, and neurodevelopmental processes has been shown (Brann et al. While estrogens are important for certain aspects of memory, however, estradiol treatment failed to improve short or long-term memory in elderly men (Matousek and Sherwin, 2010). There is evidence of de novo estrogen synthesis from cholesterol in the brain; the major site for this seem to be the neurons in the hippocampus (Fester et al. Local aromatization of testosterone leads to dynamic fluctuations in estrogen concentrations that are associated with probably nongenomic effects on various physiological and behavioral effects including social behavior and cognition (Chalovich and Eisenberg, 2005). Estrogen-Excess State in the Male the major clinical signs of estrogen excess in males are gynecomastia, testicular atrophy, erectile dysfunction, and infertility. Estrogen-secreting tumors and other endogenous or exogenous sources of estrogen can induce inhibition of testicular function by inhibiting gonadotropin secretion (Table 6). Gynecomastia the crucial factor in the development of gynecomastia from any cause may not the absolute level of estrogen but rather the ratio of estrogen to testosterone; the higher the ratio, the greater the likelihood of developing gynecomastia. Physiological gynecomastia occurs during the newborn period, during adolescence, and with advanced age. The high plasma ratio of E2 to testosterone in boys with pubertal gynecomastia is likely the result of normal aromatase activity in the testis and the extraglandular tissues before maximum production of testosterone is achieved. The prevalence of gynecomastia in older men ranges from 40% to 65% (Mathur and Braunstein, 1997; Braunstein, 2007); these may include misdiagnosed pseudogynecomastia cases, however prevalence of pseudogynecomastia has shown to be relatively low at around 5% (Dickson, 2012). With advanced age, the increased ratio of estrogen to testosterone favors feminization. However, in elderly men, it is a diagnosis of exclusion given that many elderly patients take medication or have medical problems that may contribute to breast enlargement. Pathological gynecomastia can be due to a variety of causes, resulting in an alteration of the estrogen/testosterone ratio (Table 6). When testosterone production or action is compromised, elevated plasma gonadotropin levels further alter the plasma estrogen/testosterone ratio by stimulating the testis to produce more estrogen. Liver disease, starvation, thyrotoxicosis, and adrenocortical tumors are conditions where increased amounts of aromatizable androgen. Drugs that alter the ratio of estrogen to androgen at the level of the breast can cause gynecomastia (Table 6). There also have been reports of gynecomastia in children who ingested dairy or meat products from estrogen-injected and pregnant cows (Maruyama et al. In addition, drugs that impair testosterone synthesis or action can also cause gynecomastia. Approximately 50% of the men who receive high-dose spironolactone (150 mg/day) develop gynecomastia due to inhibition of both testosterone synthesis and testosterone action (Prisant and Chin, 2005). Spironolactone at low doses (50 mg/day) may cause gynecomastia, although less commonly, by blocking androgen binding to the receptor, with less effect on testosterone synthesis. There is evidence to suggest that estrogen also plays an important role in spermatogenesis and male fertility. Estrogen appears to be important in the development and maintenance of the efferent ductules and epididymides.

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Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers womens health alliance cary ob gyn generic 35mg fosamax amex. Predictors of ovarian response: Progress towards individualized treatment in ovulation induction and ovarian stimulation. The gonad-stimulating and the luteinizing hormones of the anterior lobe of the hypophysis. Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: A prospective randomized clinical trial. Endocrinology: Sequential step-up and step-down dose regimen: An alternative method for ovulation induction with follicle-stimulating hormone in polycystic ovarian syndrome. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models. Expression of biologically active human follitropin in Chinese hamster ovary cells. Embryo transfer practices and multiple births resulting from assisted reproductive technology: An opportunity for prevention. Randomized controlled trial of preconception interventions in infertile women with polycystic ovary syndrome. Meta-analysis on the possible association between in vitro fertilization and cancer risk. Comparative in vivo and in vitro studies on the biological characteristics of recombinant human follicle-stimulating hormone. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. The effect of combined administration of chorionic gonadotropin and the pituitary synergist on the human ovary. Ovarian hyperstimulation syndrome in novel reproductive technologies: Prevention and treatment. Infertility, fertility drugs, and ovarian cancer: A pooled analysis of case-control studies. Gonadotrophin therapy for ovulation induction in subfertility associated with polycystic ovary syndrome. Individualized versus conventional ovarian stimulation for in vitro fertilization: A multicenter, randomized, controlled, assessor-blinded, phase 3 non inferiority trial. Recombinant hormones: Molecular biology and biochemistry of human recombinant follicle stimulating hormone (Puregon). Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Ovulation of a single dominant follicle during treatment with low-dose pulsatile follicle stimulating hormone in women with polycystic ovary syndrome. Practice Committee of American Society for Reproductive Medicine, Birmingham, Alabama, Birmingham, Alabama, 2008. Primary amino acid sequence of follicle-stimulating hormone from human pituitary glands I alpha subunit. Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: A meta-analysis. Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: Prospective, randomized comparison between low dose step-up and step-down dose regimens. Gonadotrophin induction of ovulation using a step-down dose regimen: Single-centre clinical experience in 82 patients. Amino acid sequence of the beta subunit of follicle-stimulating hormone from human pituitary glands. Human recombinant follicle-stimulating hormone induces growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated gonadotropin deficiency. Initial estradiol response predicts outcome of exogenous gonadotropins using a step-down dose regimen for induction of ovulation in polycystic ovary syndrome. Treatment of polycystic ovary disease with chronic low-dose follicle stimulating hormone: Biochemical changes and ultrasound correlation. Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. Ovarian stimulation in obese and non-obese polycystic ovary syndrome using a low-dose step-up regimen with two different starting doses of recombinant follicle-stimulating hormone. Ovarian Hyperstimulation Syndrome Basil C Tarlatzis, Julia K Bosdou, and Efstratios M Kolibianakis, Aristotle University of Thessaloniki, Thessaloniki, Greece r 2019 Elsevier Inc. At that point, enlarged ovaries with multiple large follicles can be detected by ultrasound. Nonsteroidal antiinflammatory agents should be avoided, as they may compromise renal function (Royal College of Obstetricians and Gynaecologists, 2016). Paracentesis under ultrasound guidance should be carried out for patients with severe discomfort, abdominal pain, respiratory distress, or oliguria due to the large amount of ascites (Royal College of Obstetricians and Gynaecologists, 2016). Symptomatic hydrothorax persisting despite abdominal paracentesis may be drained directly (Mathur and Jenkins, 2009). The duration of thromboprophylaxis should be individualized according to patient risk factors and outcome of treatment (Royal College of Obstetricians and Gynaecologists, 2016; Practice Committee of the American Society for Reproductive Medicine, 2016). Thus, currently reported mortality rates are likely to represent an underestimation of the real problem. This is feasible by identifying known risk factors for its occurrence and by classifying patients accordingly. However, the absence of corpora lutea stimulation results in low steroids levels and is associated with a decreased probability of pregnancy after fresh embryo transfer (Tarlatzis et al. By synthesizing the results from all available studies until November 2015, prospective and retrospective (Bodri et al. In such a scenario, deferring embryo transfer to a subsequent cycle is mandatory and probably beneficial since subsequent embryo transfer will take place during a normal luteal phase. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Pulmonary manifestations of severe ovarian hyperstimulation syndrome: a multicenter study. Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates. Ovarian salvage in bilaterally complicated severe ovarian hyperstimulation syndrome. Reassurance of safety of letrozole and suggested approaches in controlled ovarian hyperstimulation. Mono-ovulation in women with polycystic ovary syndrome: a clinical review on ovulation induction. Triggering with human chorionic gonadotropin or a gonadotropin-releasing hormone agonist in gonadotropin-releasing hormone antagonist-treated oocyte donor cycles: findings of a large retrospective cohort study. Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasinghormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study. Increased capillary permeability induced by human follicular fluid: a hypothesis for an ovarian origin of the hyperstimulation syndrome. Triggering of final oocyte maturation with gonadotropin-releasing hormone agonist or human chorionic gonadotropin. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a "freeze-all" strategy: a prospective multicentric study. No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles. Letrozole versus clomiphene citrate for unexplained infertility: a systematic review and meta-analysis. Triggering ovulation with gonadotropin-releasing hormone agonist in in vitro fertilization patients with polycystic ovaries does not cause ovarian hyperstimulation syndrome despite very high estradiol levels. Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice.