Paul Gisbert Auwaerter, M.B.A., M.D.

• Clinical Director, Division of Infectious Diseases
• Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0000525/paul-auwaerter

Hence hair loss in men 50 1 mg propecia with mastercard, there must be a threshold effect for estradiol in men hair loss vegan diet discount propecia 1mg overnight delivery, and this effect must be time dependent hair loss cats order propecia 1mg fast delivery. Acquired deficiencies in estrogen hair loss gastric sleeve purchase propecia 5mg fast delivery, such as occur with anorexia nervosa or chemotherapy-induced ovarian dysfunction hair loss cure october 2015 generic propecia 5mg mastercard, result in low peak bone mass and lead to subsequent risk for osteoporosis hair loss cure book buy cheap propecia 1 mg line. Probably the best study that addressed this issue comes from a retrospective analysis of men in their 30s who underwent late onset of puberty. These data suggest that both timing and quantity of gonadal steroids are critical for bone acquisition. To mineralize newly synthesized bone, calcium must become bioavailable to the skeletal matrix. In experimental studies in rodents and humans, it is clear that the several pools of available calcium are markedly enhanced during puberty. These sources include calcium efflux from the gastrointestinal tract and the calcium pool available for incorporation in the matrix. Genetic Factors That Determine Peak Bone Mass Probably the most important determinant of peak bone mass, albeit one that has lacked clear definition, is the genetic contribution. As noted earlier, low peak bone mass may be the most important pathogenic factor in the osteoporosis syndrome of later life. Further, it appears that at least 50% of peak bone mass is determined by genetic factors. They include the following: (1) a quantifiable phenotype, (2) heterogeneity within a given population under study, and (3) the polygenic nature of the disorder. Large homogeneous and heterogeneous populations are now being studied to ascertain genetic determinants of bone density in humans. Depending on the cohort, the phenotype, and the number of individuals studied, there are likely to be hundreds of genes that contribute to individual variation in bone mass. Notwithstanding, there has been a major effort to consolidate studies from around the world to increase power and detect rare variants that might provide even greater insight into genetic determinants, and importantly shed greater light on the biology of low bone mass. Twin studies examining discordant or concordant phenotypes are also helpful, as are sibling-pair studies, although the results have been disappointing. As a consequence, -catenin is stabilized, accumulates, and translocates into the nucleus, where it regulates transcription of osteoblastic genes. In addition to the search for osteoporosis genes, intervention studies in adolescents have provided insight into the environmental impact on genetic determinants. One commonly used algorithm in the United States is within the guidelines developed by the National Osteoporosis Foundation354 (see Table 30. First, osteoporosis therapy can reduce fracture risk by as much as 50%, but this means that some people will continue to have fractures despite treatment. Second, lifestyle and pharmacologic interventions may be long-term commitments, and therefore cost, compliance, and safety must be factored into therapeutic decisions. Studies suggest that with weekly or monthly oral bisphosphonate therapy, more than 40% of individuals treated will not continue therapy beyond 1 year. General Measures Diet Calcium Calcium supplementation should be an adjunct to drug treatments for women with established osteoporosis and must be part of any prevention strategy to ameliorate bone loss. Increased calcium intake reduces the secondary hyperparathyroidism often seen with advancing age and can enhance mineralization of newly formed bone. Evidence that calcium and vitamin D together or individually reduce fracture risk in the osteoporotic individual remains somewhat controversial. With intakes greater than 2000 mg/day, the risk of nephrocalcinosis certainly increases. Vitamin D Vitamin D is essential for skeletal maintenance and for enhancement of calcium absorption. Insufficiency of this vitamin is a growing problem; as many as two thirds of all patients who have hip fractures are classified as vitamin D deficient. In a large population-based study with calcium and vitamin D, supplementation had no effect on nonvertebral fractures,361 although compliance and assessment of vitamin D levels were not sufficiently well documented to exclude an effect. Besides the potentially positive effects of vitamin D supplementation on the skeleton, particularly in older women, vitamin D may reduce the risk of falling, although there continues to be significant controversy over the effect size, as noted in a recent meta-analysis. However, in those patients with low bone mass and insufficient or deficient 25-hydroxyvitamin D levels. Vitamin D analogues have been used in the treatment of osteoporosis since the early 1980s. Other studies have found little benefit with a narrow therapeutic window, particularly in relation to renal function and hypercalcemia. Currently, vitamin D analogues are not recommended for the routine treatment of osteoporosis. Physical Activity Bed rest or immobility, particularly in elderly persons, can result in rapid bone loss. Moreover, the number of falls increases with age, and the number of falls that result in fractures also rises. A meta-analysis by the Cochrane Review Group demonstrated that Chapter 30 Osteoporosis: Basic and Clinical Aspects 1293 muscle strengthening, balance retraining, home hazard assessment, withdrawal of psychotropic medications, and use of a multidisciplinary risk factor assessment program are beneficial in protecting against falls. Hip protectors have been shown to reduce the risk of hip fractures in at least one population, although compliance is generally poor. A more recent study failed to demonstrate the efficacy of these devices in older women in an assisted living facility. However, studies to date have been inconclusive with respect to understanding how changes in these lifestyles affect overall fracture risk. Notwithstanding, some promising data support the use of Tai Chi to enhance balance and reduce falls and fractures. Significant concern has been noted about the nonskeletal risks associated with long-term estrogen and estrogen in combination with progesterone. Particularly troublesome is the increased risk of breast cancer with the long-term use of estrogen and progesterone. Moreover, the availability of newer and effective antiresorptive drugs for the treatment of osteoporosis has lessened enthusiasm for primary hormonal therapy in osteoporotic women. Selective Estrogen Receptor Modulators Pharmacologic Approaches to the Treatment of Osteoporosis Abundant evidence indicates that an aggressive intervention program can be successful in reducing fracture risk and in improving quality of life among postmenopausal women with preexisting osteoporosis. Several pharmacologic options are available, and they can be classified by their mechanism of action. Antiresorptive Agents Antiresorptives inhibit bone resorption by suppressing osteoclast activity. Slowing the remodeling cycle allows bone formation to catch up to resorption, thereby enhancing matrix mineralization and stabilizing trabecular microarchitecture. Estrogen Estrogen replacement therapy was long considered the cornerstone of therapy for postmenopausal women with osteoporosis. However, there is also compelling evidence from at least two groups that osteoclasts have estrogen receptors and that estrogen blocks apoptosis of osteoclasts. Conversely, progesterone is a necessary part of hormone replacement therapy Selective estrogen receptor modulators, such as tamoxifen and raloxifene, also inhibit bone resorption by the same mechanisms used by estradiol. Both of these agents block the actions of estrogen on the breast but act like an estrogen agonist in bone; tamoxifen, but not raloxifene, has estrogen agonistic properties on the uterus and is associated with a greater risk of endometrial carcinoma with long-term use. Tissue selectivity with these selective estrogen receptor modulators and others being investigated is a subject of great scientific interest. Raloxifene and estradiol both bind to the same region of the estrogen receptor, but they induce different conformational changes in that receptor. Differing coactivating and corepressing proteins are recruited to these receptor-ligand complexes, and it is thought that these coactivators and corepressors ultimately determine the activity of the nuclear complexes. Because recruitment also depends on cell type, it is highly likely that significant tissue selectivity exists for these partners. Newer agents have been designed to facilitate particular complexes and rearrangements within the nucleus; they are being studied at both preclinical and clinical levels. These drugs are carbon-substituted analogues of pyrophosphate that bind tightly to hydroxyapatite crystals. It is thought that these agents directly suppress resorption by inhibiting osteoclast attachment and enhancing programmed cell death. Neither is approved for the treatment of osteoporosis in the United States, although etidronate is used off label and in Europe. The drug has few gastrointestinal side effects, and vertebral fracture risk reduction is significant with this agent. Recent clinical trials have shown that these drugs can be safely administered for at least 5 years without adversely affecting bone strength. Moreover, discontinuation of alendronate after 5 years results in minimal bone loss over the ensuing 5 years without a significant increase in fracture risk. Once-weekly administration of alendronate has been shown to reduce the prevalence of drug-induced esophagitis, and currently both alendronate and risedronate are marketed as once-weekly treatments. The former is given orally in a single monthly dose (150 mg) or intravenously every 3 months (3 mg). Compliance with the once-monthly regimen is higher than with the weekly dosing, although long-term data are not encouraging that this effect persists. First-dose hypersensitivity can occur with ibandronate, and because it is a nitrogen-containing bisphosphonate, it is also associated with esophageal reflux. It is administered as a single intravenous infusion over 15 minutes (5 mg) once yearly. Large randomized controlled trials have unequivocally established antifracture efficacy for hip, spine, and other nonspine fractures. Both newer bisphosphonates can cause side effects with the first dose, including joint pain, stiffness, and low-grade fevers. In addition, it should not be used in patients with a reduced glomerular filtration rate (<30 mL/minute) and should be used with caution in the elderly. Intravenous zoledronate has been approved for the treatment of malignant hypercalcemia, multiple myeloma, and skeletal metastases. Other bisphosphonates are available for off-label use or are being studied for the treatment of osteoporosis. Intravenous pamidronate has been available since the mid-1990s for the treatment of Paget disease and malignant hypercalcemia. Acute and delayed-type hypersensitivity reactions can occur with this drug, and its use is contraindicated in patients who are vitamin D deficient because it can precipitously drop serum calcium-a concern that also applies to use of zoledronic acid and denosumab. Prodromal symptoms of hip or thigh pain and associated cortical thickening or beaking in the shaft of the proximal femur are risk indicators of these fractures, which with minimal trauma can have devastating consequences in terms of quality of life and mobility. Some guidelines recommend prophylactic rod placement to prevent fractures in high-risk individuals in the ipsilateral and contralateral femora. Currently, the prevalence of this fracture is not well established, although meta-analyses suggest that there is a causal association with bisphosphonate use. However, in osteoporosis patients, the prevalence is estimated to be less than 1 in 100,000 patients exposed to oral or intravenous bisphosphonates who are otherwise healthy. Patients with dental procedures that invade bone, such as tooth implantation and tooth extraction, are at increased risk. Concomitant treatment with glucocorticoids likely enhances the risk, and infection often accompanies the necrosis. Osteoclasts have calcitonin receptors, and calcitonin can rapidly inhibit bone resorption. Salmon calcitonin is more potent than human and is the preferred treatment choice. Nasal and subcutaneous calcitonin are both approved for the treatment of postmenopausal osteoporosis. However, the evidence favoring a strong effect from this hormone on either bone loss or fracture efficacy is lacking. In at least one placebo-controlled study, nasal calcitonin reduced the pain associated with new spine fractures. Side effects are uncommon with intranasal calcitonin and include nasal stuffiness and flushing. Strontium Ranelate Strontium ranelate is orally administered and stimulates calcium uptake in bone while it inhibits bone resorption. It is thought to have some anabolic activity, although the precise mechanism Chapter 30 Osteoporosis: Basic and Clinical Aspects 1295 of action in the skeleton, where it is incorporated, is not known. Strontium ranelate has been associated with increased risk of severe allergic skin reactions, venous thromboembolism, stroke, and heart ischemia. The European Medicine Agency has decided to restrict the use of strontium ranelate only to patients with severe osteoporosis who cannot be treated with other drugs approved for osteoporosis. The agency has also warned about the necessity of regular medical care and advised the discontinuation of therapy in those patients who develop heart or circulatory problems, including high blood pressure or angina. As expected, it has maintained the recommendation against using strontium ranelate in individuals with antecedent of cardiovascular disorders. Unlike bisphosphonates, denosumab does not persist in the skeleton and hence needs to be administered once every 6 months to maintain its efficacy. In fact, discontinuation of denosumab can lead to a rebound increase in bone resorption but no increase in fractures. Importantly, fractures of spine were reduced by 70%, and nonvertebral fractures, including hip fractures, were also significantly reduced. Surprisingly, long-term studies (in 2015, out to 8 years in the extension trial) have failed to show significant adverse events for this agent, although atypical femoral fractures occur. Odanacatib, one cathepsin K inhibitor, has been tested in postmenopausal women with osteoporosis and is shown to be an effective suppressor of bone resorption. Interestingly, women treated with odanacatib have suppressed bone resorption but no change or a slight increase in bone formation. This may be due to the finding that this agent blocks the breakdown of collagen but does not kill osteoclasts; hence, signals from osteoclasts to osteoblasts may be maintained, thereby preserving bone formation.

Management of undescended testes: European Association of Urology/European Association for Paediatric Urology Guidelines hair loss in men 1920 purchase propecia 1 mg overnight delivery. Acquired undescended testes and fertility potential: is orchidopexy at diagnosis better than awaiting spontaneous descent Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants hair loss hiv cheap propecia 1 mg line. Environmental influences on ovarian dysgenesis - developmental windows sensitive to chemical exposures hair loss in men giving order 5mg propecia otc. Effects of exposure to acetaminophen and ibuprofen on fetal germ cell development in both sexes in rodent and human using multiple experimental systems hair loss 8 year old boy order propecia 5 mg with visa. Anogenital distance and penile length in infants with hypospadias or cryptorchidism; comparison with normative data hair loss cure man propecia 5mg without prescription. Experimental models of testicular development and function using human tissue and cells hair loss with lupus cheap propecia online amex. Risk of cryptorchidism among sons of horticultural workers and farmers in Denmark. A French collaborative controlled study of a cohort of 300 consecutive children without genetic defect. A path forward in the debate over health impacts of endocrine disrupting chemicals. Low dose mixture effects of endocrine disruptors and their implications for regulatory thresholds in chemical risk assessment. Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union. Advances in the molecular pathophysiology, genetics, and treatment of primary ovarian insufficiency. The molecular complexity of primary ovarian insufficiency aetiology and the use of massively parallel sequencing. Congenital adrenal hyperplasia due to 21 hydroxylase deficiency: from birth to adulthood. Incidence and clinical features of congenital adrenal hyperplasia in Great Britain. Congenital adrenal hyperplasia due to 21hydroxylase deficiency: a paradigm for prenatal diagnosis and treatment. New management strategy of pregnancies at risk of congenital adrenal hyperplasia using fetal sex determination in maternal serum: French cohort of 258 cases (2002-2011). Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. Long-term outcome of prenatal dexamethasone treatment of 21-hydroxylase deficiency. Cognitive and motor development of children with and without congenital adrenal hyperplasia after early-prenatal dexamethasone. Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish children and adolescents at risk of congenital adrenal hyperplasia. A diagnosis not to be missed: nonclassic steroid 11-hydroxylase deficiency presenting with premature adrenarche and hirsutism. History of aromatase: saga of an important biological mediator and therapeutic target. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. Recurrent maternal virilization during pregnancy caused by benign androgen-producing ovarian lesions. Clinical aspects of Mayer-Rokitansky-Kuester-Hauser syndrome: recommendations for clinical diagnosis and staging. Typical and atypical associated findings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome. Persistent unexplained congenital clitoromegaly in females born extremely prematurely. International networks for supporting research and clinical care in the field of disorders of sex development. Predictors of posttraumatic stress in parents of children diagnosed with a disorder of sex development. Implementation of a liquid chromatography tandem mass spectrometry assay for eight adrenal C-21 steroids and pediatric reference data. Gonadal malignancy in 202 female patients with disorders of sex development containing Y-chromosome material. Gonadal tumour risk in 292 phenotypic female patients with disorders of sex development containing Y chromosome or Y-derived sequence. Improving the communication of healthcare professionals with affected children and adolescents. Attitudes towards "disorders of sex development" nomenclature among affected individuals. Global disorders of sex development update since 2006: perceptions, approach and care. Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model. Timing and nature of reconstructive surgery for disorders of sex development-introduction. Presence of germ cells in disorders of sex development: implications for fertility potential and preservation. Fertility after highdose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation. The impact of and successes of a paediatric endocrinology fellowship program in Africa. Adult women with 21-hydroxylase deficient congenital adrenal hyperplasia, surgical and psychological aspects. Timing of surgery for feminizing genitoplasty in patients suffering from congenital adrenal hyperplasia. Relationship between final height and health outcomes in adults with congenital adrenal hyperplasia. Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency: a Swedish population-based national cohort study. Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia; epidemiological studies in a nonbiased national cohort in Sweden. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with congenital adrenal hyperplasia. Increased psychiatric morbidity in women with complete androgen insensitivity syndrome or complete gonadal dysgenesis. Psychosexual development in adolescents and adults with disorders of sex developmentresults from the German clinical evaluation study. Normal Growth Overview Growth is a fundamental, intrinsic aspect of childhood health. But growth and final height can also be affected by external factors, including the quality and quantity of nutrition, and by psychosocial factors. This process is regulated by multiple hormones and growth factors interacting with an array of membrane receptors that activate seemingly redundant intracellular signaling cascades. There do appear to be seasonal variations of growth, with slower growth in autumn and winter and greater growth in spring and early summer. Deviation from such a normal pattern of growth can be the first manifestation of a wide variety of disease processes, including endocrine and nonendocrine disorders and involving virtually any organ system of the body. Therefore frequent and accurate assessment of growth is of primary importance in the care of children. Measurement Assessment of growth requires accurate and reproducible determinations of height. Supine length is routinely measured in children younger than 2 years of age, and erect height is assessed in older children. It can be useful to measure both length and height in children between 2 and 3 years of age to allow comparisons with prior length measurements and to begin to record height measurement for ongoing comparisons. The inherent inaccuracies involved in measuring length in infants are often obscured by the rapid skeletal growth during this period. When children are old enough (and physically capable) to stand erect, it is best to use a wall-mounted Harpenden stadiometer similar to that designed by Tanner and Whitehouse for the British Harpenden growth study. The traditional measuring device of a flexible arm mounted to a weight balance is notoriously unreliable and does not provide accurate serial measurements. The child should be fully erect, with the head in the Frankfurt plane; the back of the head, thoracic spine, buttocks, and heels should touch the vertical axis of the stadiometer, and the heels should be together. Every effort should be made to correct discrepancies related to lordosis or scoliosis. Ideally, serial measurements should be made at the same time of day, because standing height may undergo diurnal variation. Height determinations should be performed by a trained individual rather than an inexperienced member of the staff. We recommend that lengths and heights be measured in triplicate, that variation should be no more than 0. For determination of height velocity when several measurements are being made within a short period, the same individual should perform the determinations to eliminate interobserver variability. Even when every effort is made to obtain accurate height measurements, a minimum interval of 6 months is necessary for meaningful height velocity computation. Nine to 12 months of data are preferable so that errors of measurement are minimized and the seasonal variation in height velocity is assimilated into the data. There are, however, two limitations of these charts when applied to the individual child. First, they do not satisfactorily define children below the 3rd or above the 97th percentiles-the very children in whom it is most critical to define the degree to which they deviate from the normal growth centiles. For example, a short child below the 3rd percentile can be described more precisely as being, for example, approximately 4. Second, crosssectional data are of greater value during infancy and childhood than in adolescence, because differences in the timing of pubertal onset can considerably influence normal growth rates. To address this issue, Tanner and Davies10 developed longitudinal growth charts in an effort to construct the curve shapes with centile widths obtained from a large cross-sectional survey, thus accounting for variability in the timing of puberty. Such charts are of particular value in assessing growth during adolescence and puberty and for plotting sequential growth data for any individual child. It is important to emphasize that carefully documented height velocity data are invaluable in assessing a child with abnormalities of growth. There is considerable variability in normal height velocity of children at different ages; however, between the age of 2 years and the onset of puberty, children grow with remarkable fidelity relative to the normal growth curves. Any crossing of percentile curves on the height chart during this age period should be considered abnormal and warrants further evaluation. Body Proportions Many abnormal growth states, including both short stature and excessive stature, are characterized by disproportionate growth. Upper body segment: the difference between total height and lower body segment (it can also be measured as the sitting height, subtracting the height of the chair or stool) 4. Parental Target Height Genetic factors are important determinants of growth and height potential. Because of regression to the mean,17,18 children of short parents are likely to be less short than their parents, and children of tall parents are likely to be less tall than their parents. In more than 95% of children, the adult height falls within 10 cm of the point thus calculated. This forms the basis of the bone age or skeletal age, a quantitative determination of net somatic maturation that serves as a mirror of the tempo of growth and maturation. The bone age also reflects the degree of growth plate senescence and is therefore a useful adjunct in estimating growth opportunity. Karlberg and associates resolved the normal linear growth curve into three additive, partially superimposable phases27,28: an "infancy" phase, starting in midgestation and then rapidly decelerating until about 3 to 4 years of age; a "childhood" phase, of slowly decelerating growth through early adolescence; and a sigmoid-shaped "puberty" phase that comprises the adolescent growth spurt. The height difference between men and women, an average of 13 cm, is accounted for by two factors. First, boys grow for an average of 2 years longer than girls, because girls have an earlier onset of puberty and, consequently, earlier cessation of growth. The 97th, 50th, and 3rd percentile curves define the general pattern of growth during puberty. Shaded areas indicate velocities in those children with peak velocities occurring up to 2 standard deviations before or after the average age depicted by the percentile lines. The solid line depicts the actual linear growth rate; the dashed line connecting the prenatal and postnatal length velocity lines depicts the theoretic curve for no uterine restriction late in gestation. After puberty, chondrocyte proliferation in the growth plate slows and senescence occurs due to depletion of stem-like cells in the resting zone of the growth plate. In many cases, it is difficult to differentiate children with these normal growth variants from children with a growth disorder. Crossing Linear Percentiles of Infancy As in postnatal growth, genetic and environmental factors are important determinants of fetal growth and of the size of an infant (weight and length) at birth. However, there are significant differences between the factors affecting birth size and those affecting childhood growth and adult stature. There is much less correlation between length at birth and ultimate adult height than between length at birth and height in the later years of childhood. Although maternal and paternal stature contribute equally to childhood growth and adult stature, the effect of maternal stature may predominate over that of paternal stature on length at birth.

Testosterone improves antidepressant-emergent loss of libido in women: findings from a randomized hair loss in men jobs purchase propecia american express, double-blind hair loss cure home remedies order propecia 1 mg with amex, placebo-controlled trial hair loss young men propecia 5 mg discount. Prevalence and incidence of prolonged and severe dyspareunia in women: results from a population study hair loss in men due to iron deficiency cheap propecia online amex. Morphometry of the pelvic floor muscles in women with and without provoked vestibulodynia using 4D ultrasound hair loss usa water buy propecia 5mg. The recurrent pain and sexual sequelae of provoked vestibulodynia: a perpetuating cycle hair loss in men treatment purchase propecia 1 mg with mastercard. Provoked vestibulodynia: psychological predictors of topical and cognitive-behavioral treatment outcome. Long-term results of an individualized, multifaceted, and multidisciplinary therapeutic approach to provoked vestibulodynia. The stress model of chronic pain: evidence from basal cortisol and hippocampal structure and function in humans. Understanding migraine through the lens of maladaptive stress responses: a model disease of allostatic load. Psychological profiles among women with vulvar vestibulitis syndrome: a chart review. Vulvar vestibulitis: medical, psychosexual and psychosocial aspects, a case-control study. Surgical and behavioral treatments for vestibulodynia: two-and-one-half year follow-up and predictors of outcome. Cognitivebehavioral therapy for women with lifelong vaginismus: a randomized waiting-list controlled trial of efficacy. Therapist-aided exposure for women with lifelong vaginismus: a randomized waiting-list control trial of efficacy. An integrated mindfulness-based approach to the treatment of women with sexual pain and anxiety: promoting autonomy and mind/body connection. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebocontrolled trial. Libigel (testosterone gel) does not differentiate from placebo therapy in the treatment of hypoactive sexual desire in postmenopausal women. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance and physical function in a randomized trial. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial. Efficacy and safety of on-demand use of 2 treatments designed for different etiologies of female sexual interest/arousal disorder: 3 randomized clinical trials. Androgen therapy for loss of desire in women: is the benefit worth the breast cancer risk Management of female sexual dysfunction in postmenopausal women by testosterone administration: safety issues and controversies. Endogenous androgen levels and cardiovascular risk profile in women across the adult life span. Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. Challenging atrophied perspectives on postmenopausal dyspareunia: a systematic description and synthesis of clinical pain characteristics. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Vaginal estriol-lactobacilli combination and quality of life in endocrine-treated breast cancer. Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased libido in women receiving aromatase inhibitors for early-stage breast cancer: a randomized clinical trial. Evaluation of the efficacy and safety of hyaluronic acid vaginal gel to ease vaginal dryness: a multicenter, randomized, controlled, open-label, parallel-group, clinical trial. Moisturisers, lubricants, and vulvar hygiene products: issues, answers and clinical implications. Microdose transdermal estrogen therapy for relief of vulvovaginal symptoms in postmenopausal women. Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: a systematic review and meta-analysis. Introduction During the last decade there has been increasing public awareness of individuals whose gender identity is not aligned with their physical sex characteristics. Concurrently there has been an increasing number of gender nonconforming/transgender individuals seeking medical services to enable development of physical sex characteristics consistent with their affirmed gender identity. For some people, their gender identity does not fit neatly into one of those two choices. This is an umbrella term used when the gender identity and/or gender expression differs from what is typically associated with the designated gender. These terms refer only to the surgical part of gender-confirming/gender-affirming treatment. Gender expression Gender identity/experienced gender Gender identity disorder Gender incongruence Gender variance Gender reassignment Gender-reassignment surgery (genderconfirming/genderaffirming surgery) Gender role Sex designated at birth Sex this refers to behaviors, attitudes, and personality traits that a society (in a given culture and historic period) designates as masculine or feminine and/or that society associates with or considers typical of the social role of men or women. The best-known attributes include the sex-determining genes, the sex chromosomes, the H-Y antigen, the gonads, sex hormones, internal and external genitalia, and secondary sex characteristics. This is an umbrella term for people whose gender identity and/or gender expression differs from what is typically associated with their sex designated at birth. This refers to individuals assigned female at birth but who identify and live as men. Sexual orientation Transgender Transgender male (also: transman, femaleto-male, transgender male) Transgender woman (also: transwoman, male-to-female, transgender female) Transition Transsexual this refers to individuals assigned male at birth but who identify and live as women. This refers to the process during which transgender persons change their physical, social, and/or legal characteristics consistent with their affirmed gender identity. This is an older term that originated in the medical and psychologic communities to refer to individuals who have permanently transitioned through medical interventions or desired to do so. Studies that shed light on biological determinants of gender identity are derived principally from three biomedical disciplines: genetics, endocrinology, and neuroscience, highlights of which are summarized in this chapter. The intent in focusing on biological underpinnings of gender identity is not to pathologize or to identify a mechanism that can be "fixed. With respect to genetics, a recent study notes heritability estimates for gender identity in the range of 30% to 60%. A psychodiagnostic evaluation is important not only to determine the presence or absence of gender dysphoria but also to assess for the presence of other mental health concerns that may co-occur. While the majority of gender dysphoric children and adolescents do not have an underlying severe psychiatric illness, it is important to recognize that there is an association of gender dysphoria and autism spectrum disorder. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. For recommendations on monitoring once pubertal induction has been completed, see Tables 21. Endocrine treatment of genderdysphoric/gender-incongruent persons: an Endocrine Society clinical practice guideline. Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. Transgender males can be treated with testosterone alone; transgender females are treated with a combination of estrogen and an agent that blocks testosterone secretion and/or action using protocols similar to those used in transgender adults (see later discussion on hormone therapy in transgender adults). With respect to estrogen treatment, 17-estradiol (transdermal, oral, or parenteral) is preferred to conjugated. Some transgender adolescents seek surgical procedures to bring their bodies into closer alignment with their gender identity. Following the completion of this three-stage approach to care, gender dysphoria was resolved, general psychologic functioning steadily improved, and a sense of well-being based on standardized survey results was noted to be equal to or greater than that seen in age-matched controls from the general population. Transgender adolescents may wish to preserve fertility, which may be otherwise compromised if puberty is suppressed at an early stage and the patient subsequently pursues physical transition with gender-affirming sex hormones. In vitro maturation of human germ cells has not yet been achieved, though promising studies have been carried out in mice. No abnormalities were seen with creatinine or with liver enzymes, and there was no change in hematocrit or hemoglobin A1c. One individual developed hyperprolactinemia, though this was seen in the context of high-dose ethinyl estradiol treatment to limit statural growth. No abnormalities were reported in blood pressure, renal and liver function studies, and hemoglobin A1c. The endocrinologist should also assist in any legal matters that arise, such as gender or name change, and referral to surgical specialists for gender-affirming surgery when the timing is appropriate. Hormone therapy protocols have been developed to mimic the sex steroid (testosterone and estradiol) concentrations in the expected reference range for males and females. Many centers around the world have utilized different preparations and delivery methods of sex steroid hormones along with adjunctive treatments to achieve this goal. Over time, these protocols have been refined and adopted by other clinics around the world. These protocols involve careful titration of hormone doses according to the blood concentrations of sex steroid hormones until a steady-state concentration is achieved. In some instances, co-management with an endocrinologist along with another hormone prescriber may be necessary if there are other coexisting mental health or medical comorbidities. The initial encounter with a transgender adult should include a history of the duration and severity of the gender dysphoria and a careful review of chronic medical issues that can be exacerbated by hormone therapy. It is important to discuss any history of depression and to assess suicide since transgender individuals are at increased risk. Finally, the endocrinologist should carefully review the letter provided from the mental health provider if the individual has already been receiving counseling. Evaluate patient every 3 months in the first year and then one to two times per year to monitor for appropriate signs of feminization and for the development of adverse reactions. For individuals on spironolactone, serum electrolytes, particularly potassium, should be monitored every 3 months in the first year and annually thereafter. Routine cancer screening is recommended, as in nontransgender individuals (all tissues present). In individuals at low risk, screening for osteoporosis should be conducted at age 60 years or in those who are not compliant with hormone therapy. Transdermal estrogen, presumed to be less stimulatory of prothrombotic proteins, is preferred in transgender women over the age of 40 due to the increased risk of thromboembolic disease. There have been no head-to-head studies that have studied these two methods of administration. In general, when hormone therapy is taken under medical supervision, the risks of adverse events are low likely due to the careful attention not to exceed supraphysiologic concentrations. Transfeminine Hormone Therapy Estrogen Several formations of estrogen have been used in the past, including synthetic estrogens. Estrogens can be given by several routes of administration, including orally, transdermally, or intramuscularly/subcutaneously (see Table 21. The most commonly prescribed and common route of administration of estrogen is oral estradiol due to its convenience, cost, and relatively good safety profile. The dose of oral estradiol is titrated to a serum estradiol range of 200 to 300 pg/mL. Testosterone-lowering agents allow for estrogen therapy to induce secondary sex characteristics unopposed from the actions of testosterone, and thus a lower dose of estrogen is required. Spironolactone is most commonly used in the United States for its widespread availability and ease of administration. It is taken orally once or twice a day in doses ranging from 100 to 300 mg total daily (see Table 21. Spironolactone was developed for its antagonism of the mineralocorticoid receptor and as a potassium-sparing diuretic. Less is known about the precise mechanism by which spironolactone lowers testosterone, but it is widely appreciated in cisgender men to cause gynecomastia likely due to antagonism of the androgen receptors, increased clearance of testosterone, increased conversion of testosterone to estradiol, and direct inhibition of testosterone production. In Europe and parts of Asia, cyproterone acetate has been commonly used as the testosterone-lowering agent. Cyproterone has progestin-like activity and lowers testosterone by lowering gonadotropin levels. A recent study in transgender girls found that cyproterone acetate monotherapy resulted in lower gonadotropins and lower total and free testosterone, which were associated with favorable physical changes, including less facial hair and increased breast growth. In addition, there have been concerns regarding an increased risk of sexual dysfunction and depression as reported in cisgender men. However, 5-reductase inhibitors may have a role in transgender women who have androgenetic alopecia and who do not achieve an adequate response to spironolactone. Several websites and forums have suggested that progesterone may enhance breast development and areolar darkening based on anecdotal reports. A populationbased survey of more than 100 transgender women living in New York City revealed that 17% of transgender women were taking progesterone. Physicians and other clinicians should discuss the known risks of progesterone with transgender women who ask for progesterone therapy and make a shared decision of whether a trial of progesterone is indicated. Evaluate patient every 3 months in the first year and then one to two times per year to monitor for appropriate signs of virilization and for development of adverse reactions. Measure serum testosterone every 3 months until levels are in the normal physiologic male rangea: a. For testosterone enanthate/cypionate injections, the testosterone level should be measured midway between injections. Alternatively, measure peak and trough levels to ensure levels remain in the normal male range.

Hysterosonography and hysteroscopy are not appropriate tests to evaluate endometrial hyperplasia or cancer because these procedures may cause dissemination of malignant cells hair loss in menopausal women buy cheap propecia 1mg online. If malignancy is suspected hair loss in men 50s fashion propecia 5mg visa, it should be ruled out by an office endometrial biopsy (see Table 17 hair loss girl discount 1 mg propecia with visa. Occasionally an office endometrial biopsy cannot be performed or is not diagnostic of endometrial neoplasia hair loss treatment yahoo answers buy propecia with amex. In these rare instances curezone hair loss purchase generic propecia from india, endometrial curettage under anesthesia is performed for a reliable tissue diagnosis hair loss cure keith cheap propecia 5mg visa. A careful history and physical examination may eliminate the need for most of these diagnostic tests. Before ordering a certain diagnostic study, it is useful to consider whether a particular test result would alter the ultimate clinical management. Management of Anovulatory Uterine Bleeding If ovulatory function can be restored, anovulatory bleeding usually gives way to predictable cyclic periods. Because restoration of ovulatory function may not be possible or practical in many of these women, exogenous estrogen and progestin are administered for several purposes. The indications for hormonal treatment of uterine bleeding include the need to stop acute uterine bleeding, to maintain predictable bleeding episodes, or to prevent endometrial hyperplasia. Various anatomically demonstrable pathologic involvements of the genital tract (see Table 17. Bleeding because of a coagulation defect usually consists of a heavy flow with regular, cyclic menses. Other tests should be ordered on the basis of the initial clinical evaluation, including tests to evaluate anovulatory disorders of various causes (see Table 17. Pelvic ultrasonography through a vaginal probe is an extremely useful test for the evaluation of normal or abnormal pregnancy, uterine leiomyomas, endometrial neoplasia, and ovarian tumors (see Table 17. Other imaging studies may be used judiciously to rule out pathologic involvement of the hypothalamus, pituitary, and adrenal (discussed earlier). Advanced adenomyosis is associated with diffuse enlargement of the uterus, hypermenorrhea, and anemia. Oral Contraceptives Use of combination oral contraceptives in an acute or chronic fashion is the most common treatment for irregular uterine bleeding. The estrogen component of the combination pill stabilizes the endometrial tissue and stops shedding within hours; it decreases ovarian secretion of sex steroids by suppression of gonadotropins within several days. The progestin component of the pill directly affects endometrial tissue to decrease shedding over days and potentiates ovarian suppression induced by estrogen. The progestin (in the presence of estrogen) induces differentiation of the endometrial tissue into a stable form called pseudodecidua. Typically, a monophasic oral contraceptive preparation that contains 30 or 35 g of ethinyl estradiol is preferred. Triphasic oral contraceptives and those with less than 30 g of ethinyl estradiol are not suitable for the treatment of excessive anovulatory uterine bleeding. A combination oral contraceptive in high doses (two or three pills per day) can be used for short intervals. Oral Contraceptives and Acute Excessive Uterine Bleeding Associated With Anemia Unopposed estrogen exposure in women with anovulatory uterine bleeding is commonly associated with chronic endometrial buildup and heavy bleeding episodes. Therapy is administered as Chapter 17 Physiology and Pathology of the Female Reproductive Axis 627 one combination oral contraceptive pill twice daily for 1 week. In case of anovulatory bleeding, the flow does diminish rapidly within 2 days after the beginning of high-dose oral contraceptive treatment. Specific causes of anovulation and possible coagulation disorders should be evaluated during the next few days. The physician should also consider whether blood replacement or initiation of iron therapy is necessary. The patient should also be warned of possible nausea that may be caused by high-dose oral contraceptive treatment. At the end of a week of high-dose oral contraceptive treatment, the pill is stopped temporarily. On the third day of this withdrawal bleeding, a regular dose of combination oral contraceptive medication (one pill/day) is started. This is repeated for several 3-week treatments interrupted by 1-week withdrawal intervals. Regardless of the requirement for contraception, use of oral contraceptives represents the best choice for hormonal management of heavy anovulatory bleeding and should be offered as long-term management. Before the administration of a progestin (or oral contraceptive), pregnancy should be ruled out. Alternatively, norethindrone acetate at 5 mg/day or megestrol acetate at 20 mg/day may be administered for 10 days every 2 months. A heavy progestin withdrawal flow usually follows within 3 days after the last dose is administered. Failure of progestin to correct irregular bleeding requires diagnostic reevaluation such as endometrial biopsy. Predictable withdrawal bleeding within several days after each cycle of progestin administration suggests the absence of endometrial malignancy. Hypothalamic anovulation and hyperprolactinemia are associated with low estrogen levels that are insufficient to prevent bone loss. A combination oral contraceptive is a suitable long-term treatment for both forms of chronic anovulation. Before the administration of an oral contraceptive, pregnancy should be ruled out. One pill per day is ordinarily administered for 3-week periods interrupted by 1-week hormone-free intervals. The risk of thromboembolism, stroke, or myocardial infarction associated with long-term administration is extremely low in current nonsmokers and in the absence of a history of thromboembolism. Provided that the oral contraceptive controls the abnormal uterine bleeding effectively, a chronically anovulatory woman can continue this regimen until menopause. The absence of naturally synthesized progesterone in anovulatory states is the rationale for administering a progestin. High-Dose Estrogen for Acute Excessive Uterine Bleeding An oral contraceptive given two or three times daily is the treatment of choice to stop heavy anovulatory bleeding. A high-dose oral contraceptive regimen should be offered to women with heavy uterine bleeding with or without asymptomatic anemia after anatomically demonstrable pathology of the genital tract has been ruled out (see Table 17. A patient with acute and severe anovulatory bleeding accompanied by symptomatic anemia represents a medical emergency. These patients should be hospitalized immediately and offered a blood transfusion. After genital tract disease has been ruled out by history, physical examination, and pelvic ultrasonography, intravenously administered high-dose estrogen is the treatment of choice to stop life-threatening bleeding. A wellestablished regimen is to administer 25 mg of conjugated estrogen intravenously every 4 hours until bleeding markedly slows down or for at least 24 hours. Because high-dose estrogen is a risk factor for thromboembolism, taking two or three oral contraceptive pills per day for a week or large doses of intravenous conjugated equine estrogens for 24 hours should be regarded as presenting a significant risk. However, no data are available to evaluate any risk associated with this type of acute use of hormonal therapy for such short intervals. The physician and patient should make a decision regarding high-dose hormone therapy after considering its risks and benefits. Alternative treatment options may be offered to patients with significant risk factors. High-dose hormone treatment should also be avoided in women with severe chronic illness such as liver insufficiency or renal insufficiency. One alternative for these patients is dilatation and curettage, followed by treatment with an oral contraceptive (one pill per day) until the uterine bleeding is under control. This add-back regimen is usually sufficient to prevent osteoporosis and does not ordinarily worsen the uterine bleeding. An ovarian endometrioma may decrease the quality of the eggs or become sufficiently large to interfere with the ovulation process. Clinical evidence points to a deleterious effect of uninterrupted ovulatory cycles on the development and persistence of endometriosis. Occasionally, a rectovaginal nodule remains symptomatic in a postmenopausal woman, suggesting that its persistence is independent of ovarian estrogen. In line with these observations, basic and clinical research findings indicate major roles of the ovarian steroids estrogen and progesterone in the pathologic development of endometriosis. In humans and primate models, estrogen stimulates the growth of endometriotic tissue, whereas aromatase inhibitors that block estrogen formation and antiprogestins are therapeutic. As cellular and molecular mechanisms in endometriosis are uncovered, this condition is coming to be viewed as a systemic and chronic complex disease, much like diabetes mellitus or asthma. These three types of lesions may be variant phenotypes of the same pathologic process, or they may be caused by different mechanisms. These lesions may occur singly or in combination and are associated with significantly increased risk of infertility and chronic pelvic Mechanism of Disease A number of hypotheses have been proposed regarding the histologic origin of endometriosis. Sampson suggested that fragments of menstrual endometrium pass retrograde through the tubes and then implant and persist on peritoneal surfaces. Alternatively, the coelomic-metaplasia hypothesis describes the genesis of endometriotic lesions within the peritoneal cavity by differentiation of mesothelial cells into endometrium-like tissue. A third hypothesis argues that menstrual tissue from the endometrial cavity reaches other body sites through veins or lymphatic vessels. Although most women of reproductive age have reflux menstruation into the peritoneal cavity, endometriosis is encountered in only 5% to 10% of this population. Two possible mechanisms may explain the successful implantation of refluxed endometrium on the peritoneal surface or in a hemorrhagic corpus luteum cyst of the ovary. First, the eutopic endometrium of women with endometriosis exhibits multiple subtle but significant molecular abnormalities, including activation of oncogenic pathways or biosynthetic cascades favoring increased production of estrogen, cytokines, prostaglandins, and metalloproteinases. Inflammation is a hallmark of endometriotic tissue that overproduces prostaglandins, metalloproteinases, cytokines, and chemokines. Basic biologic functions such as inflammation, immune response, angiogenesis, and apoptosis are altered in favor of survival and replenishment of endometriotic tissue. Reliable diagnosis of peritoneal endometriosis can be made only by direct visualization of these lesions by laparoscopy or laparotomy. Treatment Treatment of infertility caused by endometriosis consists of surgical removal with or without assisted reproductive technology, whereas pain is usually treated with a combination of medical suppression of ovulation and surgery. Ovarian endometriomas and rectovaginal endometriotic nodules may be effectively removed only by full dissection. Epidemiologic and laboratory data suggest a link between ovarian endometriosis and distinct types of ovarian cancers. A possible alternative mechanism of action of the androgenic steroid danazol or a progestin is a direct growth-suppressive effect on endometriotic tissue. Many patients and physicians do not favor danazol because of its anabolic and androgenic side effects of weight gain and muscle cramps and occasional irreversible virilization. Greater duration is not recommended due to a dose-dependent decrease in bone mineral density. Both doses of elagolix were also associated with other hypoestrogenic adverse effects. Because it is practical to maintain these patients on a combination oral contraceptive for years with a relatively benign side effect profile, birth control pills as a class has been the most suitable long-term management option. The radical treatment is removal of both ovaries, and even this was not found to be effective in a number of cases of postmenopausal endometriosis. First, large quantities of estrogen can be produced locally within the endometriotic cells. Moreover, endometriosis is resistant to selective effects of progesterone and progestins. Aromatase expression and local estrogen biosynthesis in endometriotic implants prompted pilot studies to target aromatase in endometriosis using its third-generation inhibitors. Among these inhibitors, anastrozole and letrozole were used successfully to treat endometriosis in postmenopausal and premenopausal women. Endometriosis is defined as the presence of endometrium-like tissue on the pelvic peritoneum (red and blue-black lesions) or in the ovary (blood-filled cyst, i. These lesions are thought to originate from abnormal endometrial tissue stem cells (blue), which have migrated retrograde during menstruation. Normal endometrial cells (red) without such survival capabilities are thought to go through apoptosis in the peritoneal or ovarian environments. It is possible that women with endometriosis have higher numbers of the abnormal cells in their eutopic endometrial tissues. Thus recurrent menstruation seems to be a significant risk factor for developing endometriosis. These epigenetic abnormalities may be inherited or caused by environmental influences such as inflammation and endocrine disruptors. A lack of promoter methylation is associated with promoter activation and the presence of extraordinarily large quantities of these nuclear receptors in endometriotic stromal cells. For the medical management of pain in premenopausal women with endometriosis, this author favors the following simple algorithm. Unless contraindicated, the continuous use of a combination oral contraceptive is the initial treatment of choice. The patient is reassured that the majority of women will have minimal or no breakthrough bleeding after 6 months of continuous oral contraceptive treatment. If adequate pain relief is not achieved after 6 months of use, a daily oral aromatase inhibitor (anastrozole 1 mg/day or letrozole 2. If pain relief is still not satisfactory, conservative laparoscopic surgery is considered.

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