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By: Bertram G. Katzung MD, PhD

  • Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco


This region modulates gene transcription by estrogen and antiestrogens zomig 5mg amex, having a role that influences 55 antiestrogen efficacy in suppressing estrogen-stimulated transcription purchase zomig 5mg mastercard. The conformation of the receptor-ligand complex is different with estrogen and antiestrogens buy zomig 5mg fast delivery, and this conformation is different with and without the F region generic zomig 5mg. The F region is not required for transcriptional response to estrogen; however, it affects the magnitude of ligand-bound receptor activity. It is speculated that this region affects conformation in such a way that protein interactions are influenced. Thus, it is appropriate that the effects of the F domain vary according to cell type and protein context. Mechanism of Action the steroid family receptors are predominantly in the nucleus even when not bound to a ligand, except for the androgen, mineralocorticoid, and glucocorticoid receptors where nuclear uptake depends on hormone binding. But the estrogen receptor does undergo what is called nucleocytoplasmic shuttling. The estrogen receptor constantly diffuses out of the nucleus and is rapidly transported back in. When this shuttling is impaired, receptors are more rapidly degraded in the cytoplasm. Prior to binding, the estrogen receptor is an inactive complex that includes a variety of proteins, including the heat shock proteins. Heat shock protein 90 appears to be a critical protein, and many of the others are associated with it. This heat shock protein is not only important for maintaining an inactive state, but also for causing 57 proper folding for transport across membranes. Imagine the unoccupied steroid receptor as a loosely packed, mobile protein complexed with heat shock proteins. The conformational change induced by hormone binding involves a dissociating process to form a tighter packing of the receptor. The hormone-binding domain contains helices that form a pocket (also 54 referred to as a sandwich fold). After binding with a hormone, this pocket undergoes a conformational change that creates new surfaces with the potential to interact with co-activator and co-repressor proteins. Conformational shape is an important factor in determining the exact message transmitted to the gene. Conformational shape is slightly but significantly different with each ligand; estradiol, tamoxifen, and raloxifene each induce a distinct conformation that contributes to 58, 59 the ultimate message of agonism or antagonism. The weak estrogen activity of estriol is because of its altered conformation shape when combined with the 60 estrogen receptor in comparison with estradiol. The hormone-binding domain of the estrogen receptors contains a cavity surrounded by a wedge-shaped structure, and it is the fit into this cavity that is so influential in influencing the genetic message. The size of this cavity on the estrogen receptor is relatively large, larger than the volume of an estradiol molecule, explaining the acceptance of a large variety of ligands. Thus, estradiol, tamoxifen, and raloxifene each bind at the same site within the hormone binding domain, but the conformational shape with each is not identical. Conformational shape is a major factor in determining the ability of a ligand and its receptor to interact with coactivators and corepressors. Conformational shapes are not simply either “on” or “off,” but intermediate conformations are possible providing a spectrum of agonist/antagonistic activity. Members of the thyroid and retinoic acid receptor subfamily do not exist in inactive complexes with heat shock proteins. These mutants can form dimers with natural estrogen receptor (wild type), and then bind 61 to the estrogen response element, but they cannot activate transcription. This indicates that transcription is dependent on the result after estradiol binding to the estrogen receptor, an estrogen-dependent structural change. Molecular modeling and physical energy calculations indicate that binding of estrogen with its receptor is not a simple key and lock mechanism. It involves conversion of the estrogen-receptor complex to a preferred geometry dictated to a major degree by the specific binding site of the receptor. The estrogenic response depends on the final bound conformation and the electronic properties of functional groups that contribute energy. Estrogen, progesterone, androgen, and glucocorticoid receptors bind to their response elements as dimers, one molecule of hormone to each of the two units in the dimer. The estrogen receptor-alpha can form dimers with other alpha receptors (homodimers) or with an estrogen receptor-beta (heterodimer). Similarly, the estrogen receptor-beta can form homodimers or heterodimers with the alpha receptor. This creates the potential for many pathways for estrogen signaling, alternatives that are further increased by the possibility of utilizing various response elements in target genes. Cells that express only one of the estrogen receptors would respond to the homodimers; cells that express both could express to a homodimer and a heterodimer. An important part of the conformational pattern consists of multiple cysteine-repeating units found in two structures, each held in a finger like shape by a zinc ion, the so-called zinc 63 fingers Zinc fingers. Directed changes (experimental mutations) indicate that conservation of the cysteine residues is necessary for binding activity, as is the utilization of zinc. The activity of the hormone-responsive element requires the presence of the hormone-receptor complex. There are at least four different hormone-responsive elements, one for glucocorticoids/progesterone/androgen, one for estrogen, one for 64 vitamin D3, and one for thyroid/retinoic acid. The polymerase transcription factor complex can be developed in sequential fashion with recruitment of individual polypeptides, or transcription can result from interaction with a preformed complete complex. Chromatin factors — structural organizational changes that allow an architecture appropriate for transcription response.

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Hypospadias in the absence of any other deformity is not included in this classification zomig 5mg lowest price. Rarer causes of female pseudohermaphroditism are excess maternal androgen caused by drug ingestion discount zomig 5mg with amex, tumor secretion discount zomig 5mg with mastercard, or possibly aromatase deficiency cheap zomig 5mg with visa. Congenital Adrenal Hyperplasia (the Adrenogenital Syndrome) Congenital adrenal hyperplasia in females is characterized by masculinized external genitalia, and is diagnosed by demonstrating excessive androgen production by 38, 39and 40 the adrenal cortex, caused by either tumor or hyperplasia. Depending on the time of onset, quantity available, and duration of exposure, the presence of excessive androgens is manifested by varying degrees of fusion of the labioscrotal folds, clitoral enlargement, and anatomical changes of the urethra and vagina. Generally, the urethra and vagina share a urogenital sinus formed by the fusion of labial folds. The degree of urogenital sinus deformity is related to the timing in prenatal development of the onset of masculinizing androgen effect. Because there is no anomalous secretion of anti-müllerian hormone in females with congenital adrenal hyperplasia, the fallopian tubes, uterus, and upper vagina develop normally. Since wolffian duct development and maintenance depend on high local androgen levels provided by the male gonad, the excessive androgens of adrenal hyperplasia origin cannot stimulate this process, and no wolffian development is retained. The external genitalia on the other hand can be substantially altered by adrenal hyperplasia. After the 10th week, when the vagina and urethra have separated, the emerging excess androgen effect may be limited to clitoral hypertrophy. High androgen levels earlier than the 12th week of fetal age, however, can cause progressive fusion of the labia, formation of a urogenital sinus, and even variable closure of the urethra along the phallus (hypospadias). The absence of palpable testes may be the only clinical marker suggesting female pseudohermaphroditism. This is because the internal genitalia are completely formed by the 10 week of gestation, whereas the adrenal cortex does not reach a level of significant function until 10–12 weeks. Because the female external genitalia phenotype is not completed until 20 weeks of fetal age, early androgen excess (10–12 weeks gestation) may fully masculinize, whereas late (18–20 weeks gestation) androgen may create limited ambiguity of the basically female appearance of the urogenital sinus and genital folds. The size of the clitoris depends on the quantity rather than timing of androgen excess. Cases of incorrect sex assignment in the female are due to the similarity between these external genitalia and hypospadias and bilateral cryptorchidism in a male infant. If untreated, the female with adrenal hyperplasia will develop signs of progressive virilization postnatally. Pubic hair will appear by age 2–4, followed by axillary hair, then body hair and beard. Bone age is advanced by age 2, and because of early epiphyseal closure, height in childhood is achieved at the expense of shortened stature in adulthood. Progressive masculinization continues with the development of the male habitus, acne, deepened voice, and primary amenorrhea and infertility. In addition to sexual changes, patients can present with metabolic disorders such as salt-wasting, hypertension, or rarely, hypoglycemia. An electrolyte imbalance of the salt-losing type is usually apparent within a few days of birth and occurs in approximately two-thirds of patients with virilizing adrenal hyperplasia. Beginning with a refusal to feed, failure to thrive, apathy, and vomiting, the infant goes on to an Addisonian-like crisis with hyponatremia, hyperkalemia, and acidosis. Less frequent is hypertension, which occurs in approximately 5% of patients with virilizing adrenal hyperplasia. Virilizing adrenal hyperplasia is the result of an inherited abnormality of steroid biosynthesis that results in an inability to synthesize glucocorticoids. This stimulation induces a hyperplastic adrenal cortex that produces androgens as well as corticoid precursors in abnormal quantities. Therefore, one can see a well-compensated infant who has achieved normal cortisol levels but at the expense of extensive masculinization. In summary, the clinical picture resulting from a specific enzyme deficiency is due to the effects of both the inadequate production of cortisol/aldosterone and excess accumulation of precursors, with diversion into biosynthetic pathways yielding androgens. The most common enzymatic defects are the 21-hydroxylase (P450c21), the 11b-hydroxylase (P450c11), and the 3b-hydroxysteroid dehydrogenase types. The 21-hydroxylase block is the most common form of congenital adrenal hyperplasia (95% of cases), the most frequent cause of sexual ambiguity, and the most frequent endocrine cause of neonatal death. With severe uncompensated blocks of this type, salt-wasting and shock accompany significant virilization. In less severe variations, when sufficient cortisol can be produced, virilization due to excess androgen is still present in utero, at birth, or later in life. Three different clinical forms are recognized representing the spectrum of severity: the salt-wasting, the simple virilizing, and the nonclassical (previously known as the late-onset, attenuated, or acquired adrenal hyperplasia). The first and second are associated with female pseudohermaphroditism at birth, while the third usually becomes apparent at adolescence or beyond and causes hirsutism, menstrual irregularities, and infertility. Most patients are compound heterozygotes, having a different genetic lesion on each copy of chromosome 6, one from each parent. The severity of the condition is determined by the activity of the least affected allele. Salt-wasting, simple virilizing, and nonclassical clinical manifestations, respectively, are due to the most, less, and the least deficiency of 21-hydroxylase. Finally, heterozygotes for either the mild or severe deficiency exhibit the mildest enzyme deficiency and are clinically asymptomatic. In classic 11b-hydroxylase deficiency, 11-deoxycortisol is not converted to cortisol. Accumulated precursors are shunted into androgen biosynthesis with virilization similar to that seen with 21-hydroxylase deficiency. This pathway is used in the zona glomerulosa to synthesize aldosterone, and the degree to which aldosterone levels are affected lends clinical heterogeneity to the classic presentation of 11b-hydroxylase deficiency (virilization, hypertension, volume overload).

This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results generic zomig 5mg online. A complete assessment of quality of individual studies requires critical appraisal of all aspects of the study design 5 mg zomig visa. Patients treated one way (eg discount zomig 5 mg with mastercard, cemented hip arthroplasty) compared with a group of patients treated in another way (eg cheap zomig 5 mg without a prescription, unce- mented hip arthroplasty) at the same institution. Patients identifed for the study based on their outcome, called “cases” (eg, failed total arthroplasty) are compared to those who did not have outcome, called “controls” (eg, successful total hip arthroplasty). Patients treated one way with no comparison group of patients treated in another way. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. Grades of Recommendations for Summaries or Reviews of Studies A: Good evidence (Level I Studies with consistent fnding) for or against recommending intervention. I: Insufcient or conficting evidence not allowing a recommendation for or against intervention. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. Search results with abstracts will be compiled by the medi- port development of recommendations for appropriate clinical cal librarian in Endnote sofware. The medical librarian typically care or use of new technologies is the comprehensive literature responds to requests and completes the searches within two to search. A comprehensive search of the evidence will be conducted obtain requested full-text articles for review. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. Early rehabilitation compression without fusion in spondylolytic spondylolis- targeting cognition, behavior, and motor function afer lumbar thesis: Long-term results of Gill’s procedure. Contemporary management of versus instrumented spondylodesis in the treatment of sciatica isthmic spondylolisthesis: pediatric and adult. Aunoble S, Hoste D, Donkersloot P, Liquois F, Basso Y, Le Huec in J Bone Joint Surg Br. Single-level posterolateral arthrodesis, with or ous pedicle screw fxation for adult low-grade isthmic spon- without posterior decompression, for the treatment of isthmic dylolisthesis: minimum 3 years of follow-up. Extraforaminal lumbar interbody fusion for confguration of the sacrum in spondylolisthesis. Lower back pain in the athlete: Common con- rior migration of fusion cages in degenerative lumbar disease ditions and treatment. Radio- pedicle instrumented lumbar fusion afer a two year postopera- graphic analysis of newly developed degenerative spondylolis- tive follow up. Arnold P, Winter M, Scheller G, Konermann W, Rumetsch D, of the Royal Army Medical Corps. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. In situ instrumented [Lumbo-sacral spondylolysis and spondylolisthesis in children. Single-level posterolateral arthrodesis, with or tional and radiographic follow-up of surgically treated isthmic without posterior decompression, for the treatment of isthmic spondylolisthesis. Minimum acceptable outcomes afer tional and radiographic follow-up of surgically treated isthmic lumbar spinal fusion. The natural history of spondylolysis and Diagnosis, natural history, and nonsurgical management. Comparison of the results of spinal randomized clinical study with a 5-year follow-up. Jun 15 fusion for spondylolisthesis in patients who are instrumented 2002;27(12):1269-1277. Defects of pars interartic- followinglumbar/thoracolumbar fusion with pedicle screw ularis in athletes: a protocol for nonoperative treatment. Complications associated with posteri- kyphosis reduction, decompression, and posterior lumbosacral or lumbar interbody fusion using Bagby and Kuslich method for transfxation in high-grade isthmic spondylolisthesis: clinical treatment of spondylolisthesis. Italian Journal of Orthopaedics and Trau- a case report and review of the literature. Low back pain in school-age children: to surgical methods, choice of implant and postoperative risk factors, clinical features and diagnostic managment. Journal of Manual and alignment using a wedged carbon fber reinforced polymer Manipulative Terapy. This clinical guideline should not be construed as including all proper methods of care or excluding or other acceptable methods of care reason- ably directed to obtaining the same results. Hybrid lumbar fusion: A spondyloptosis: implications for spondylolisthesis progression. The long-term efect of postero- of isthmic lumbar spondylolisthesis in young patients. Predictive factors for the sion of isthmic lumbar spondylolisthesis in young patients. Predictive factors for the posterior lumbar fusion with pedicle screws and posterior outcome of fusion in adult isthmic spondylolisthesis.

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But in cases of true fracture or if symptoms do not resolve refraining from these sports activities may be required for 3-6 months generic 5 mg zomig visa. Dynamed (2017) reports that there is midlevel evidence that stopping sports activity for ≥ 3 months is associated with better pain improvement than stopping sports for < 3 months cheap zomig 5 mg with visa. Orthosis (bracing) Bracing is a commonly recommended intervention (Dynamed 2017 generic zomig 5mg online, Kurd 2007) purchase zomig 5 mg line, but high-level evidence is lacking. A 2009 meta-analysis of children and young adults treated conservatively for spondylolysis and spondylolisthesis found that 83. In these pooled results from observational trials, bracing did not seem to affect patient outcomes. Bracing can be considered in patients who continue to have symptoms despite an initial period of rest. Additional indications for the consideration of using an external brace are presence of a true fracture, the presence of spondylolisthesis, or lack of patient compliance to activity restrictions (Malanga 2016). If a brace is used, some authorities suggest it is more effective if applied as soon as possible. In a 2015 study of children (ages 5-14), treatment included wearing a brace all day except at bedtime. The patient is slowly weaned off it as symptoms resolve even if the fracture has healed in nonunion. Patients were allowed to sleep without the brace if symptoms were not exacerbated. This was compared to conservative management, which included the use of a conventional soft lumbar corset for 3-6 months. Follow-up radiographs showed healing without the use of a rigid brace in 73% of the patients in the early stage, in 38. Bouras (2015) suggests that the athlete’s compliance with treatment and relative rest protocol may be more important than which particular type of brace is used. Physical Rehabilitation Dynamed (2017) reports that there is mid-level evidence that a low back physical rehabilitation focusing on stabilizing back exercises may decrease pain intensity and functional disability in symptomatic patients with isthmic spondylolysis. The rehabilitation program is initiated after symptoms begin to resolve and the bone has had some time to recover, but it should not be delayed too long. One retrospective study (Selhorst 2016) found that adolescent athletes with acute spondylolysis who were referred to physical therapy sooner than after 10 weeks of rest, the median period for full return to activity was almost 25 days shorter than for those who waited for more than 10 weeks. And there was no statistically significant difference in the risk of adverse reactions seen between the two groups. The exercise program is essentially the same as for treatment for spondylolisthesis; see page 11. Spondylolisthesis is almost never due to trauma (Malanga 2016) and most commonly is isthmic in young patients and degenerative in older patients. Spondylolisthesis is likely asymptomatic in most adult patients (only about 10% of adult patients with spondylolisthesis reported to have symptoms that require treatment) (Dynamed) and so an incidental finding on a radiograph may be worth charting as a complicating factor (especially by a manual therapist) but may not be relevant to the patient’s symptoms. Clinical Tip: Spondylolisthesis is an unlikely cause of back pain in adults (especially after age 40) with no history of symptoms before age 30 years; usually, another diagnosis must be identified . In the case of dysplastic spondylolisthesis, the defect more often is at the L5-S1 junction. A step defect discovered during the physical has a reported test sensitivity ranging from 60-88% and a specificity of 87-100% in an athlete population. A positive test is pain or feeling of heaviness in the low back that disappears when the leg is lowered. Degenerative spondylolisthesis is more common in women than in men (5-6X) (Vibert 2006), although men demonstrate radiographic instability more frequently than women. In most cases, patients do not complain of symptoms suggesting neurologic deficit with lower grades of spondylolisthesis. Nerve roots can be affected by the local expansion of scar tissue in the healing defect or tractioned when there is slippage of the vertebral body. The nerve root compression in these cases may be due to hypertrophic fibrous or osseous tissue filling in the pars defect. In one cohort of 111 patients with symptomatic spondylolisthesis awaiting surgery, 62% had sciatica (Möller 2000). If significant listhesis is present, radicular syndromes, though uncommon, do occur; cauda equina syndrome is even a rarer complication. The L5 nerve root is the most commonly involved, followed by the L4 nerve root in more severe cases (with weakness in the tibialis anterior muscle). In some cases of chronic spondylolisthesis, weight loss may be recommended to decrease ventral load on lumbar spine (Dynamed 2017). Orthosis (bracing) Dynamed (2017) reports that there is level 3 evidence that back bracing leads to cessation in back pain in patients with grade 1-2 spondylolisthesis. Indications of spinal joint dysfunction and myofascial pain generators should be assessed and treated accordingly, aside from acknowledging the presence the spondylolisthesis which may or may not be the pain generator. Patients with spondylolisthesis respond at a rate similar to other forms of mechanical low back pain, with an 80% success rate compared to a 77% success rate for general non-specific low back cases. The practitioner may find that the patient generally tolerates manipulation and patient positioning that favor flexion over extension. The spinous process of the vertebra above is lifted cephalad as the table is flexed causing local distraction. Three 20-second distraction sessions are applied, each session consisting of 5-6 cycles of distraction. A typical treatment schedule for this therapy would be about 8 weeks, 3 times a week. As a general rule, physical rehabilitation program should not be started until after an adequate rest period and once pain with daily activities has subsided (Perin 2016).

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A laparoscopic approach to total hysterectomy is preferable to an abdominal approach as it is B associated with a shorter hospital stay buy zomig 5mg with amex, less postoperative pain and quicker recovery generic zomig 5mg amex. There is no benefit from intraoperative frozen section analysis of the endometrium or routine C lymphadenectomy cheap 5mg zomig amex. Postmenopausal women with atypical hyperplasia should be offered bilateral salpingo-oophorectomy P together with the total hysterectomy buy 5 mg zomig visa. For premenopausal women, the decision to remove the ovaries should be individualised; however, D bilateral salpingectomy should be considered as this may reduce the risk of a future ovarian malignancy. Endometrial ablation is not recommended because complete and persistent endometrial destruction C cannot be ensured and intrauterine adhesion formation may preclude endometrial histological surveillance. How should women with atypical hyperplasia who wish to preserve their fertility or who are not suitable for surgery be managed? Women wishing to retain their fertility should be counselled about the risks of underlying malignancy P and subsequent progression to endometrial cancer. Pretreatment investigations should aim to rule out invasive endometrial cancer or co-existing ovarian P cancer. Histology, imaging and tumour marker results should be reviewed in a multidisciplinary meeting and P a plan for management and ongoing endometrial surveillance formulated. How should women with atypical hyperplasia not undergoing hysterectomy be followed up? Review schedules should be D individualised and be responsive to changes in a woman’s clinical condition. Review intervals should be every 3 months until two consecutive negative biopsies are obtained. In asymptomatic women with a uterus and evidence of histological disease regression, based upon a P minimum of two consecutive negative endometrial biopsies, long-term follow-up with endometrial biopsy every 6–12 months is recommended until a hysterectomy is performed. Disease regression should be achieved on at least one endometrial sample before women attempt to P conceive. Women with endometrial hyperplasia who wish to conceive should be referred to a fertility specialist D to discuss the options for attempting conception, further assessment and appropriate treatment. Assisted reproduction may be considered as the live birth rate is higher and it may prevent relapse C compared with women who attempt natural conception. Prior to assisted reproduction, regression of endometrial hyperplasia should be achieved as this is B associated with higher implantation and clinical pregnancy rates. Subsequent management should be as described in the preceding sections of the guideline. Discuss the limitations of the available evidence regarding the optimal progestogen regimen in this context. Subsequent management should be as described in the preceding sections of the guideline. How should endometrial hyperplasia be managed in women on adjuvant treatment for breast cancer? What is the risk of developing endometrial hyperplasia on adjuvant treatment for breast cancer? Women taking tamoxifen should be informed about the increased risks of developing endometrial D hyperplasia and cancer. They should be encouraged to report any abnormal vaginal bleeding or discharge promptly. How should women who develop endometrial hyperplasia while on tamoxifen treatment for breast cancer be managed? The need for tamoxifen should be reassessed and management should be according to the histological P classification of endometrial hyperplasia and in conjunction with the woman’s oncologist. Complete removal of the uterine polyp(s) is recommended and an endometrial biopsy should be D obtained to sample the background endometrium. Subsequent management should be according to the histological classification of endometrial P hyperplasia. Purpose and scope the aim of this guideline is to provide clinicians with up-to-date evidence-based information regarding the management of endometrial hyperplasia. Introduction and background epidemiology Endometrial hyperplasia is defined as irregular proliferation of the endometrial glands with an increase in the gland to stroma ratio when compared with proliferative endometrium. Further information about the assessment of evidence and the grading of recommendations may be found in Appendix I. Endometrial hyperplasia is often associated with multiple identifiable risk factors and assessment P should aim to identify and monitor these factors. Endometrial hyperplasia develops when estrogen, unopposed by progesterone, stimulates endometrial cell growth by binding to estrogen receptors in the nuclei of endometrial cells. This separates D endometrial hyperplasia into two groups based upon the presence of cytological atypia: i. Classification systems for endometrial hyperplasia were developed based upon histological characteristics and oncogenic potential. The association of cytological atypia with an increased risk of endometrial cancer has been known since 1985. What diagnostic and surveillance methods are available for endometrial hyperplasia? Diagnosis of endometrial hyperplasia requires histological examination of the endometrial tissue. B Endometrial surveillance should include endometrial sampling by outpatient endometrial biopsy. Diagnostic hysteroscopy should be considered to facilitate or obtain an endometrial sample, especially P where outpatient sampling fails or is nondiagnostic. Transvaginal ultrasound may have a role in diagnosing endometrial hyperplasia in pre- and P postmenopausal women. Direct visualisation and biopsy of the uterine cavity using hysteroscopy should be undertaken where P endometrial hyperplasia has been diagnosed within a polyp or other discrete focal lesion.

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