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cat lady

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  1. I posted about Henry VIII a while back. There were a bunch of articles on him about a year ago or so. And I vote for Sally Struthers. Poor woman has been picked on for years.
  2. How Should a Nonfunctioning Pituitary Macroadenoma be Monitored After Debulking Surgery? Yona Greenman; Naftali Stern Published: 09/10/2009 Summary and Introduction Summary Transsphenoidal surgery is the treatment of choice for nonfunctioning pituitary macroadenomas but is seldom curative. Tumour progression rates are high in patients with postoperative remnants. Therefore, long-term monitoring is necessary to detect tumour growth, which may be asymptomatic or manifest with visual field defects and/or pituitary dysfunction. In view of the generally slow-growing nature of these tumours, yearly magnetic resonance imaging, neuro-ophalmologic and pituitary function evaluation are appropriate during the first 3-5 years after surgery. If there is no evidence for tumour progression during this period, testing intervals may be extended thereafter. Introduction Most clinically nonfunctioning pituitary adenomas (NFPA) are of gonadotroph cell origin, but rarely manifest with clinical signs or symptoms related to gonadotropin excess. Headaches, visual field compromise and decrease in visual acuity, as well as hypopituitarism are the most common presenting features of NFPA, and are all induced by pressure of the tumour on surrounding structures. Therefore, tissue decompression is the main therapeutic goal in NFPA, being effectively achieved in most cases through transsphenoidal excision of the tumour. Nevertheless, these usually large and invasive tumours often cannot be completely resected. NFPA patients need long-term surveillance, although the best means and frequency of follow-up have not been clearly established. The monitoring strategy used in our institution and presented herein has evolved based on published observational studies on the natural history of NFPA, and clinical experience. The Problem of Lack of Secretory Markers In clinically functioning pituitary adenomas, circulating hormone levels are accurate tumour markers. Hence, the presence of elevated serum hormone concentration may indicate incomplete surgical resection or tumour recurrence even in face of an apparently normal imaging study. This important tool is lacking for the follow-up of most NFPA, as elevated gonadotropins are detected only in a minority of patients on basal conditions, and the TRH-induced increase in β-subunits is not a sufficiently reliable marker for the presence of residual tumour.[1] Consequently, detection of recurrence or residual tumour growth relies directly on imaging studies, or is indirectly based on appearance of new defects or deterioration of previously impaired visual and pituitary function. Early Postoperative Assessment Visual Fields Resolution of headaches and amelioration of visual field defects occur shortly after surgery in the majority of patients. The recovery of visual fields is progressive, with an early fast phase of improvement during the first week after surgery, an early slow phase (4-6 months postoperatively) by the end of which most of the eventual recovery takes place and a late phase (up to 3-5 years) in which mild further improvement may still occur.[2] Overall, normalization of visual function occurs in 35-39% and improvement in 50-60% of patients.[2,3] Worsening of vision is reported in 0?5-2?4% of patients, and as with other surgical complications, its prevalence depends on the experience of the neurosurgeon and the volume of operations performed in a particular centre.[4] Based on these data, a neuroophthalmological assessment should be performed 1 week and again after 3-6 months following surgery. The visual status obtained in these evaluations will be the baseline for subsequent comparisons. Pituitary Function In most[5] but not all[6] series, normalization of one or more hypothalamo-pituitary-axis function has been reported after surgery, whereas worsening of pituitary function is less common. The degree of improvement is variable, occurring in 15-50% of patients.[5] This variability probably reflects the actual degree and duration of the preoperative impairment, surgical expertise, the use of different endocrine tests and criteria for the diagnosis of hypopituitarism as well as the surgical route of operation. Pituitary function normalized in 19?6%, improved in 30?1%, remained unchanged in 48?9% and worsened in 1?4% of patients following surgery by the transsphenoidal route; whereas after transcranial surgery, none of the patients had normalization, only 11?3% had improvement and 15% had deterioration of pituitary function, as reported by Nomikos et al.[7] Transient diabetes insipidus (DI) complicates up to 15% of surgeries, but permanent DI is less frequent, occurring in 0?9%[8] to 2% of patients. Transient hyponatremia secondary to ADH excess may occur in the context of a triphasic pattern of DI or as an isolated event, peaking at postoperative day 7.[9] During the immediate postoperative period (7-10 days), emphasis should focus on evaluation and correction of corticotroph and posterior pituitary deficits. The recovery of the hypothalamo-pituitary adrenal-axis occurs very early in the postoperative period, as ACTH levels increase within hours after surgery in patients who recover adrenal function,[10] and an insulin tolerance test (ITT) performed within 8 days after surgery was 100% sensitive and specific in predicting long-term normalcy of the axis.[11] In practice, morning serum cortisol levels are measured 3-7 days after surgery depending on the schedule of perioperative glucocorticoid coverage, and indicate the need for continuing steroid replacement until definitive testing is performed. Thus, morning cortisol levels less than 100 nmol/l or over 450 nmol/l are consistent with ACTH deficiency and sufficiency, respectively, and intermediate levels require further testing.[12] ACTH stimulation tests, while easier and safer than ITT, are not a reliable enough means to detect new onset of postoperative secondary hypoadrenalism in the first 4-6 weeks, as adrenal cortical mass and response may be still preserved during this time interval, but the low-dose 1 μg ACTH test is a powerful and sensitive tool thereafter.[13] The time frame for recovery of other hypothalamo-pituitary-axes has not been longitudinally studied and the best timing for testing has not been established. Although this is traditionally performed 4-6 weeks after surgery,[9] the long-term predictive value of tests conducted at this time is not known. It is reasonable to re-assess the function of axes found to be impaired at the first postoperative evaluation 3, 6 and 12 months thereafter, both to assess the current status of pituitary function and need for hormone replacement, and to establish the baseline for subsequent follow-up. Imaging Early postoperative magnetic resonance images (MRI) are difficult to interpret owing to intrasellar fluid and blood collection, the presence of implanted sealing materials and incomplete descent of residual suprasellar tumour remnants. Therefore, the completeness of tumour resection and assessment of remnant size are better achieved by MRI performed at least 3-4 months after surgery.[14] In some cases, even at this point, the distinction between adenomatous tissue and postoperative changes and fibrosis may be difficult. In this context, 11C-methionine PET, which detects protein synthesis in viable tissue, could be helpful, but its place in the management of pituitary tumours needs further validation.[15] The initial postoperative MRI will be the baseline against which subsequent imaging will be compared with for the detection of recurrence or tumour progression. Long-term Monitoring The long-term follow-up strategy is based on the slow-growing nature of NFPA and on the reported rates of recurrence or tumour remnant progression. The calculated tumour volume doubling time (TVDT) is variable and ranges from 0?8 to 27?2 years.[16] Patients with TVDT under 5 years were younger (50 ? 15 years) than those with TVDT over 5 years (69 ? 7 years).[17] The true recurrence/progression rate of NFPA is difficult to assess because of selection bias (more aggressive tumours being referred to radiotherapy)[18] and variable surveillance methods. Most series are retrospective in nature and lack a pre-established protocol for imaging intervals. Tumour growth may be detected earlier, at an asymptomatic stage, through serial MRI imaging, or later, when patients present with mass-related symptoms. Despite these caveats, patients in whom complete tumour resection has been achieved have, in general, a low risk for recurrence, whereas those with residual tumours have high long-term progression rates (13% and 41%, respectively).[5] Longer follow-up duration is associated with increased detection of recurrence/progression.[6] The mean time for detection of tumour progression varies between 2?2 and 7?5 years ( Table 1 ), ranging from 6 months to 20 years. Some clinical aspects, such as young age[3] and extent of suprasellar extension in the residual tumour,[19] have been associated with a higher risk of tumour enlargement. This may indicate the need for more careful surveillance for these patients. Nevertheless, in general, our ability to predict tumoural biological behaviour is poor. Morphological features in the pathologic specimen, such as cytological atypia, and presence of mitoses do not reliably reflect tumour aggressiveness. Similarly, markers of cell proliferation, such as Ki-67, PCNA and p53, do not consistently correlate with tumour invasiveness or recurrence.[20,21] Therefore, we perform MRI yearly for the first 3-5 years after surgery in all patients, for the detection of more rapidly growing tumours. The detection of an increase in tumour mass not leading to prompt re-operation will require a repeat imaging study at an earlier time. In the absence of such progression, however, imaging intervals may be then spaced to every 2 years and later on to every 3 years, as at this point we are dealing with stable or very slow growing tumours. Technical aspects of MRI interpretation and tumour size evaluation should be established a priori and standardized to allow for accurate comparisons over time. Another aspect to be emphasized is the need to compare the most current imaging study not only with the previous, but also with earlier studies, as this is the only way to reliably detect small size changes over time. Visual field testing should be performed generally every 12 months, especially when the tumour margins are in relative proximity to the optic chiasm, or in between imaging studies in other instances. More frequent visual assessment is needed for tumours quite adjacent to the optic chiasm, as appearance of new or deterioration of existing visual field defects is reported in nearly half of the patients in whom tumour growth occurs during conservative follow-up.[22] Pituitary function should also be assessed on a yearly basis, as it may become compromised with tumour growth. Table 1. Postoperative Recurrence of NFPA Not Treated With Radiation, According to Degree of Surgical Resection, in Series in Which Time to Recurrence Was Specified Series Ref. N No residual tumour in postoperative MRI Residual tumour Recurrence Mean time to detection (year) 5 year RFS (%) Growth Mean time to detection (year) 5 year PFS (%) 10 year PFS (%) Soto-Ares et al. (2002) 27 51 0/17 (0) 13/34 (38?2) 2?2 ? 1?4 60?9 Greenman et al. (2003) 19 108 6/30 (20) 5 ? 2 84 41/78 (52?5) 2?2 ? 1?1 30 Dekkers et al. (2006) 6 97 0/27 (0) 9/70 (12?8)* 6?3 92 74 Ferrante et al. (2006) 28 150? 14/73 (19?2) 7?5 ? 2?6 45/77 (58?4) 5?3 ? 4 Van den Bergh et al. (2007) 29 28 16/28 (57) 2?5 49 22 Total 434 20/147 (13?6) 124/287(43) Values in parentheses are percentages. RFS = recurrence-free survival; PFS = progression-free survival. *Including six patients who received radiation therapy and had no evidence of tumour growth. ?After exclusion from the initial cohort of patients who received radiation therapy or were reoperated. Does Treatment Choice Affect Monitoring? Patients in whom tumour has been completely excised usually undergo expectant follow-up as recurrence rates are low, as detailed earlier. In contrast, the optimal management of patients in whom residual tumour is detected on postoperative MRI is controversial, and may include observation alone,[6] the use of dopamine agonists (DA)[23] or radiation therapy.[24] Discussion on the merits or indications for the different therapeutic approaches is beyond the scope of this document. Nevertheless, the choice of treatment may influence some aspects of long-term monitoring. For example, particular attention should be given to pituitary function evaluation of irradiated patients in view of the high incidence of radiation-related hypopituitarism that is insidious and may take up to 20 years to develop.[24] Patients on DA therapy may need periodic echocardiograms in view of the increased incidence of valvular heart disease reported in cabergoline treated patients with Parkinson's disease,[25] although the lower doses used for treatment of pituitary disease have not generally been associated with clinically significant alterations in most studies.[26] Radiation and DA treatment reduce tumour progression rates to 8-20%[5] and 21%, respectively,[23] but because the anatomical response of an individual tumour to therapy cannot be anticipated, the imaging strategy should be similar to that of untreated patients. [ CLOSE WINDOW ] References 1. Greenman, Y., Tordjman, K., S?mjen, D. et al. (1998) The use of β-subunits of gonadotrophin hormones in the follow-up of clinically non-functioning pituitary tumours. Clinical Endocrinology, 49, 185-190. 2. Gnanalingham, K.K., Bhattacharjee, S., Pennington, R. et al. (2005) The time course of visual field recovery following transsphenoidal surgery for pituitary adenomas: predictive factors for a good outcome. Journal of Neurology, Neurosurgery and Psychiatry, 76, 415-419. 3. Losa, M., Mortini, P., Barzaghi, R. et al. (2008) Early results of surgery in patients with nonfunctioning pituitary adenomas and analysis of the risk of tumor recurrence. Journal of Neurosurgery, 108, 525-532. 4. Ciric, I., Ragin, A., Baumgartner, C. et al. (1997) Complications of transsphenoidal surgery: results of a national survey, review of the literature and personal experience. Neurosurgery, 40, 225-236. 5. Molitch, M.E. (2008) Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinology and Metabolism Clinics of North America, 37, 151-171. 6. Dekkers, O.M., Pereira, A.M., Roelfsema, J.H.C. et al. (2006) Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. Journal of Clinical Endocrinology and Metabolism, 91, 1796-1801. 7. Nomikos, P., Ladar, C., Fahlbusch, R. et al. (2004) Impact of primary surgery on pituitary function in patients with non-functioning pituitary adenomas - a study on 721 patients. Acta Neurochirurgica, 146, 27-35. 8. Nemergut, E.C., Zuo, Z., Jane, J.A. et al. (2005) Predictors of diabetes insipidus after transsphenoidal surgery: a review of 881 patients. Journal of Neurosurgery, 103, 448-454. 9. Ausiello, J.C., Bruce, J.N. & Freda, P.U. (2008) Postoperative assessment of the patient after transsphenoidal pituitary surgery. Pituitary, 11, 391-401. 10. Arafah, B.M., Kailani, S.H., Nekl, K.E. et al. (1994) Immediate recovery of pituitary function after transsphenoidal resection of pituitary macroadenomas. Journal of Clinical Endocrinology and Metabolism, 79, 348-354. 11. A., R.J., Shewbridge, R.K. & Shepherd, M.D. (1997) Which patients benefit from provocative adrenal testing after transsphenoidal pituitary surgery? Clinical Endocrinology, 46, 21-27. 12. Inder, W.J. & Hunt, P.J. (2002) Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. Journal of Clinical Endocrinology and Metabolism, 87, 2745-2750. 13. Kazlauskaite, R., Evans, A.T., Villabona, C.V. et al. (2008) Corticotropin tests for hypothalamic-pituitary-adrenal insufficiency: a metaanalysis. Journal of Clinical Endocrinology and Metabolism, 93, 4245-4253. 14. Kremmer, P., Forsting, M., Ranaei, G. et al. (2002) Magnetic resonance imaging after transsphenoidal surgery of clinically nonfunctional pituitary macroadenomas and its impact on detecting residual adenoma. Acta Neurochirurgica (Wien), 144, 433-443. 15. Tang, B.N.T., Levivier, M., Heureux, M. et al. (2006) 11C-methionine PET for the diagnosis and management of recurrent pituitary adenomas. European Journal of Nuclear Medicine and Molecular Imaging, 33, 169-178. 16. Honegger, J., Zimmermann, S., Psaras, T. et al. (2008) Growth modeling of non-functioning pituitary adenomas in patients referred for surgery. European Journal of Endocrinology, 158, 287-294. 17. Tanaka, Y., Hongo, K., Tada, T. et al. (2003) Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index. Journal of Neurosurgery, 98, 359-365. 18. Turner, H.E., Stratton, I.M., Byrne, J.V. et al. (1999) Audit of selected patients with nonfunctioning pituitary adenomas treated without irradiation - a follow-up study. Clinical Endocrinology, 51, 281-284. 19. Greenman, Y., Ouaknine, G., Veshchev, I. et al. (2003) Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth. Clinical Endocrinology, 58, 763-769. 20. Gejman, R., Swearingen, B. & Hedley-Whyte, E.T. (2008) Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Human Pathology, 39, 758-766. 21. Dubois, S., Guyetant, S., Penei, P. et al. (2007) Relevance of Ki-67 and prognostic factors for recurrence/progression of gonadotropic adenomas after first surgery. European Journal of Endocrinology, 157, 141-147. 22. Karavitaki, N., Collison, K., Halliday, J. et al. (2007) What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clinical Endocrinology, 67, 938-943. 23. Greenman, Y., Tordjman, K., Osher, E. et al. (2005) Postoperative treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists decreases tumour remnant growth. Clinical Endocrinology, 63, 39-394. 24. Gittoes, N.J.L. (2003) Radiotherapy for non-functioning pituitary tumors- when and under what circumstances? Pituitary, 6, 103-108. 25. Zanettini, R., Antonini, A., Gatto, G. et al. (2007) Valvular heart disease and the use of dopamine agonists for Parkinson's disease. New England Journal of Medicine, 356, 39-46. 26. Molitch, M.E. (2008) The cabergoline-resistant prolactinoma patients: new challenges. Journal of Clinical Endocrinology and Metabolism, 93, 4643-4645. 27. Soto-Ares, G., Cortet-Rudelli, C., Assaker, R. et al. (2002) MRI protocol technique in the optimal therapeutic strategy of non-functioning pituitary adenomas. European Journal of Endocrinology, 146, 179-186. 28. Ferrante, E., Ferraroni, M., Castrignano, T. et al. (2006) Non-functioning pituitary adenoma database: a useful resource to improve the clinical management of pituitary tumors. European Journal of Endocrinology, 155, 823-829. 29. van den Bergh, A.C.M., van den Bergh, G., Schoorl, M.A. et al. (2007) Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy. International Journal of Radiation Oncology, 67, 863-869. [CLOSE WINDOW] Authors and Disclosures Yona Greenman and Naftali Stern, Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Yona Greenman, Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Tel: +972 36973899; Fax: +972 36973053; E-Mail: greenman@tasmc.heatlh.gov.il Clin Endocrinol. 2009;70(6):829-832. ? 2009 Blackwell Publishing
  3. VIDEO LINK Woman With Hormone Condition Stands 6-Feet, 6-Inches; Weighs 476 Pounds A woman suffering from a rare hormonal disorder stands 6-feet, 6-inches, weighs 476 pounds and is still growing, the Daily Mail reports. Tanya Angus is believed to be one of the tallest and heaviest women on the planet and doctors say her condition cannot be stopped by medication. Angus, who appeared on NBC's Today show in June, lives in Nevada and suffers from a condition known as acromegaly, also referred to as gigantism. At 20-years-old, Angus stood 5-foot, 11-inches and weighed just 115 pounds, but her height and her weight soon started to spiral out of control. Her doctor diagnosed her with gigantism and she was sent to a specialist, the Daily Mail reported. RELATED: Doctor Discovers Man's Brain Tumor Through 'Spongy' Handshake An MRI scan showed she had a tumor the size of a grapefruit in her brain which had wrapped itself around her inner carotid artery, causing an overproduction of growth hormones. In 2003, she underwent surgery to remove most of the tumor, although small parts of it were too difficult to separate from her brain. She was then given a cocktail of drugs to try to control the huge amounts of growth hormones still in her body. Her growth hormones totaled 3,000. An average person has about 250. Despite the drugs, her growth hormone level has never fallen below 900. At 6ft6ins and 34stone, meet one of the largest and heaviest women on the planet - and she's still growing Standing at 6ft 6ins and weighing 34 stone, this woman has been dubbed a modern-day giant - and, alarmingly, she is still growing. Tanya Angus, who suffers from a rare growth condition, is already one of the tallest and heaviest women on the planet. Now doctors say she is the only woman in the world whose growth cannot be halted by medication. Suffering from a rare disease known as Acromeglia, a condition often referred to as 'gigantism', (which means her body is producing too much growth hormone), Tanya rocketed from a slender 5ft 8ins at the age of 18 to a massive 6ft 6ins and 34 stone. 'I'm staying hopeful,' says 30-year-old Tanya, from Nevada, USA. 'Without hope you don't have anything. I hope they can stop me growing one day so I can try to live as normally as possible.' Tanya's troubles began in her late teens when she noticed that her feet, face and figure were continuing to grow at an alarming rate. 'I started to feel unhappy with my appearance. I started spending a fortune on make-up, trying to make myself look better. I couldn't understand why my face didn't look as attractive any more,' she said. Tanya also began suffering severe migraines and felt run down and depressed, as if she was suffering from constant flu. But though she kept going to see her GP, he believed the 20-year-old was just an attention-seeker hoping to be given anti-depressant drugs, and refused to help. Even more shockingly Tanya's figure started to alter. Her once-womanly body became larger overall, and straight up and down - like a man's. 'Someone at work actually asked me if I used to be a man,' she said. 'My voice had also changed and become deeper. I was devastated and started to feel very shy and insecure.' Things finally came to a head when her own boyfriend also asked her about her new shape, and got his mum to ask her whether she'd had a sex change. 'I was heartbroken and I decided I didn't want any more to do with him,' she said. 'I phoned my mum and said I wanted to come back to Nevada. 'As soon as my sister saw me at the airport, she knew I'd changed, and she called my mum and told her we needed to see a doctor.' The family GP immediately recognised the signs of gigantism and referred Tanya to a specialist. At that stage she was 6ft 1ins tall, and a size 14 to 16, with a size 10 feet. An MRI scan eventually showed a tumour the size of a grapefruit in her brain which had wrapped itself around her inner carotid artery, causing an overproduction of growth hormone. It was so big, doctors at first said there was nothing to be done. But Tanya's mum Karen, EMT-1 medical professional and firefighter, searched the Internet and medical publications until she finally found a doctor who said he could operate. In 2003, she Tanya finally underwent surgery to remove most of the tumour, although small parts of it were too difficult to separate from her brain. She was then given a cocktail of drugs to try to control the huge amounts of growth hormones still in her body. Tanya had a count of 3,000 of the hormones, compared to an average person's of just 250. Doctors were anxious to bring the level down to less than 1,000, but they were barely able to do that. Her height had crept up to 6ft 3ins, and she was now a size 20. Unable to walk properly, she had to live with her mother and stepfather. She barely went out and was subjected to stares and make rude comments in the street. 'It was horrible,' she said. 'My whole life had to change, and I couldn't do anything for myself any more. 'The hardest thing is that people kept thinking I was man, and calling me sir, which really annoys me. I try to dress in feminine clothes and wear make-up to look nice, but it's really hard when you're my size.' Two years later in 2005, the hormone levels again began to soar, and Tanya's mum sought out a second specialist who discovered the tumour had grown again and was now the size of an orange. She underwent further surgery, and fat from her stomach had to be used to pad out areas of brain tissue from where the tumour had been removed. Tanya was put on another set of medication to reduce the growth hormone, but her levels have never sunk to below 900 and are now over 1,000. She is now one of the world's tallest women, and also one of the heaviest. Then two years ago, Tanya also suffered a stroke, caused by the pressure her massive body was putting on her heart. She had to learn how to walk and talk again, and now suffers hearing difficulties. She recovered and went to live with her sister, but still struggles to get around, and now uses a wheelchair. 'Doctors just say there is nothing we can do for her,' said Karen. 'You don't know how many doctors we have called to try and help us. We've spent all our savings, over $200,000 (?122,300) trying to help her. 'One doctor even told me that my daughter had only two months to live. That was eight months ago, but I refused to believe it. 'I won't stop until we can find something to halt the growth.' Now Tanya has a new doctor, who she's been seeing for three months, and he is hopeful of finally finding a drug combination to slow down her growth. 'I'm doing this story because I want people to understand why I'm this way,' she says. 'It's not my fault I ended up like this. 'People even in my home town are still so hurtful, and I'd like people to be educated so they can treat me as a real person at last.' She?s 6-foot-6, 480 pounds ... and still growingTanya Angus, 30, has rare disorder that causes uncontrolled growth
  4. King size! Henry VIII's armour reveals he had a 52in girth - for which he paid a terrible price He was an immense figure in the history of England. Just how immense, however, has finally been revealed after a study of his body armour exposed Henry VIII's extraordinary vital statistics. It found that by the end of his reign the 6ft 1in Tudor king had a whopping 52in waist and 53in chest - enough to make him severely obese by modern standards. The study by the Royal Armouries coincides with a forthcoming exhibition of his supersized battle dress at the Tower of London to mark the 500th anniversary of him taking the throne. Here, Philippa Gregory reveals the heavy price he paid for being a very tubby Tudor. He was a lithe and handsome lothario who went on to acquire a truly legendary waistline. Until now, however, we haven't quite appreciated just how much larger than life Henry VIII really became. But as we approach the 500th anniversary of his coronation, new research by the Royal Armouries in Leeds reveals the full scale of his gargantuan girth. Analysing his suits of armour, many of which will be brought together in a new exhibition at the Tower of London in April, the researchers discovered that by the final years of his life, the 6ft 1in Tudor boasted a whopping 52in waist. In other words, the one-time royal pin-up was now barely taller than he was round. New research has shown that by the age of 45, Henry VII's weight had started to balloon as he suffered increasingly from chronic constipation and his body succumbed to hideous sores and repeated infections Of course, years earlier, life had started rather well for young Hal. The twentysomething Henry VIII was tall, muscle-bound and supremely fit - a talented athlete and a courageous jouster at the grand tournaments of the age. His armour from that period reveals some impressive dimensions: a 32in waist and a 39in chest. According to the Venetian Ambassador, he was 'the handsomest potentate I ever set eyes on, with an extremely fine calf to his leg . . . and a round face so very beautiful that it would become a pretty woman'. But not even Henry, who believed himself directly favoured by God, could stay young for ever. Indeed, physically and mentally, the final 15 years of his life saw the most astonishing deterioration. The golden Prince Hal became old, very likely mad - and monstrously fat. By his late 40s, he measured 48 inches around the middle and soon expanded to the colossal measurements of his twilight years. Peter Armstrong, the director of the Royal Armouries, describes him simply as 'an absolute monster'. Not that you would have known that from his portrayal by Jonathan Rhys Meyers in the recent hit TV series The Tudors. The final episode reached the mid-1530s, which meant that Henry was in his mid-40s and courting his future third wife, Jane Seymour, while still married to his second, the doomed Anne Boleyn. Expanding waistline: A suit of armour worn by the king in his early 20s But Rhys Meyers looked as slim and fresh-faced as he had at the start of the first series. In the 16th century, the life expectancy of the average man was 45. As for Henry, the new research confirms, by this age his weight had started to balloon as he suffered increasingly from chronic constipation and his body succumbed to hideous sores and repeated infections. Mentally, he was also beginning to show the first signs of madness. However, he probably did not have syphilis, as is often alleged. Nor is there any record of him being prescribed mercury, the highly toxic metal that was used to treat the disease. But he may have had Cushing's syndrome (a rare hormonal disorder) which could account for the obesity and the mental instability. And there were a host of other problems, too. I would think it likely that Henry was also experiencing bouts of impotence during his marriage to Anne Boleyn; certainly, she is said to have complained of such a problem to her brother. And while he successfully sired a son - the future Edward VI - with Jane, he never managed intercourse with wife number four, Anne of Cleves. Not surprisingly, his next marriage - to the young and sexually active Catherine Howard - was said to have rejuvenated and exhausted him. But she was executed by him for no good reason other than malice in little over a year. By this time, the King weighed more than 20st, was enduring regular and very painful enemas and had a foul-smelling open wound on his leg that the royal physicians - based on the then accepted medical knowledge - refused to let heal, believing that illness must be allowed to flow out of the body. Whenever it threatened to close up, the wound would be cut open, the flesh pulled apart and tied open with string and the abscess filled with gold pellets to keep the sore running. The constant pain must have been unimaginable and certainly goes some way to explaining the legendary royal rages that characterised Henry's later years. Armed with modern medical knowledge, historians now believe this wound, which marked the onset of Henry's long decline into chronic ill health, was the result of a varicose ulcer he developed on his left thigh in his mid-30s, probably brought on by his habit of wearing tight garters on his famously handsome legs. Alternatively, it could have been caused by a condition called chronic osteitis, a bone infection that certainly fits reports of constant ulcers opening up. In 1536, Henry also suffered a particularly nasty fall from a horse while participating in one of the tournaments he so enjoyed. He was unconscious for about two hours - a period long and worrying enough for Anne Boleyn later to blame for the miscarriage she suffered soon afterwards. Some medical historians now believe his head injury was severe enough to cause permanent brain damage. Certainly, from that time, Henry's furious temper and unpredictability got even worse. He would issue orders in the morning and then countermand them in the afternoon - then plunge into an ever darker rage on discovering his instructions had already been carried out. My own research makes me believe that some sort of brain damage also goes a long way to explaining his persecution of Anne Boleyn - accusing her of adultery (not with just one man but five), witchcraft, treason and even incest, and then insisting on her execution when almost everyone, Anne included, expected her to be granted a royal pardon. Typically, at the hour of the execution of the woman he had so adored, the King was dancing with Jane Seymour. Just a few years later, in 1540, the onset of madness could also explain the savage humiliation and botched execution (carried out by a nervous teenager with a blunt axe) of Thomas Cromwell, once the King's closest adviser. Within months, Henry bitterly regretted the execution - an irrational about face that was becoming all too common. By this time, Henry was becoming a tyrant. In writing my historical novels, I apply very strict rules of accuracy to facts when they are known. But when it comes to Henry VIII, there's just no need to invent or significantly change events to improve the story. We are faced with this extraordinarily charismatic king who married six times, who broke with the Roman Catholic Church and then went mad, all before his death at the age of 55. Indeed, it is the question of human mortality that makes history so interesting. The true story of Henry VIII is a parable of the corruption of power and the frailty of the body. He got old, he became disgusting and dangerous and he grew enormously fat. But in many ways, England's most enigmatic king remains all the more interesting for his viler features. Philippa Gregory is author of The Other Boleyn Girl (HarperCollins).
  5. Interesting article. Oddly enough, the endocrinologist that told me all my diagnostic labs were invalid and that I should get gastric bypass since medical science would never figure me out specifically told me to get a Roux-en-Y bypass because it would short circuit the brain/stomach loop of ghrelin and simple banding would not (Despite the fact that I and my husband both told him I hardly eat at all). Needless to say I tossed the GI surgeon's card he gave me and didn't follow up with him. Still, it is an interesting article. Gastric Artery Embolization Stops Weight Gain in Animal Study NEW YORK (Reuters Health) Sept 17 - In a porcine model, catheter-directed chemical embolization of the gastric artery suppressed release of ghrelin, an appetite-inducing hormone, and prevented weight gain. Researchers are hopeful that this treatment could offer a less invasive alternative to bariatric surgery. "With gastric artery chemical embolization, called GACE, there's no major surgery," lead author Dr. Aravind Arepally, from Johns University School of Medicine in Baltimore, said in a statement. "In our study in pigs, this procedure produced an effect similar to bariatric surgery by suppressing ghrelin levels and subsequently lowering appetite." In the study, reported in the September 16th online issue of Radiology, five pigs were treated with the artery-ablating compound sodium morrhuate and five were treated with saline. The assigned treatment was delivered via catheter to the gastric arteries under x-ray guidance. In the active treatment group, ghrelin levels at weeks 1, 2, 3, and 4 were significantly reduced relative to baseline values. By contrast, levels in the control group were increased at all points relative to baseline values. At 4 weeks, continued weight gain was still observed in the control group, whereas in the active treatment group weight had stabilized. "With the minimally invasive nature of the GACE procedure, further refinements could provide the ability to deliver a variety of novel agents directly to the gastric fundus that would provide sustained suppression of ghrelin," the authors conclude. Radiology 2008.
  6. Australia. I saw that too. Why is it that all these doctors aren't jumping on some kind of international doctor forum when they get stumped with something like this. We see right away about 10 things that could be wrong. MOMO, acromegaly, Cushings,...not to mention they have these BIG MEDICAL BOOKS they all had to read in order to get their degrees. Crack one open and spend a weekend reading and taking some notes and set a game plan to figure it out. I know I would as a physician.
  7. Interesting. Mine was 15 in January and 10 in April. I just haven't had the energy to deal with that issue too since I had the bad reaction to the supplements. I should though.
  8. World's Tallest Woman Dies at Age 53 The world’s tallest woman, Sandy Allen, died early this morning at a nursing home in Shelbyville, Ind., at the age of 53. No cause of death has been released, but a family friend told the Indianapolis Star that Allen had been sick for several months. Allen, who was 7-foot-7, is listed by the Guinness Book of World Records as the tallest living woman, and has appeared in the publication since the mid-1970s. She came into the world weighing an average 6.5 pounds – but her abnormal growth began soon after her birth in June 1955. By the age of 10, Allen stood at 6 feet 3 inches tall and by the age of 16 she towered over 7 feet tall. Her height was due to a tumor in her pituitary gland that caused it to release growth hormones uncontrollably, according to the world record book. At the age of 22, she underwent surgery to correct the condition. When a tumor produces too much of one or more hormones, several conditions can occur including gigantism, the National Institutes of health reported on its Web site. In her first letter to the Guinness Book of World Records in 1974, Allen wrote, “I would like to get to know someone that is approximately my height. It is needless to say my social life is practically nil and perhaps the publicity from your book may brighten my life.” Following the letter, there was an offer from film director Federico Fellini to take a role in his film "Casanova" in 1975, and then her first date with a 7 foot Illinois man. In the last years of her life, Allen suffered from poor circulation and weak leg muscles which resulted in her being dependent on a wheelchair.
  9. Measurement of urinary free cortisol by tandem mass spectrometry and comparison with results obtained by gas chromatography-mass spectrometry and two commercial immunoassays Lisa Wood1, David H Ducroq2, Helen L Fraser2, Scott Gillingwater3, Carol Evans1, Alan J Pickett1, Derek W Rees1, Rhys John1 and Atilla Turkes1 1 Department of Medical Biochemistry and Immunology, University Hospital of Wales, Heath Park, Cardiff CF14 4XW, UK; 2 WEQAS, Reference Laboratory, The Quadrant Centre, Cardiff Business Park, Llanishen, Cardiff CF14 5WF, UK; 3 Waters Corporation, MS Technologies Centre, Atlas Park, Simonsway, Manchester M22 5PP, UK Corresponding author: Dr A Turkes. Email: atilla.turkes@cardiffandvale.wales.nhs.uk Background: Determination of urinary free cortisol (UFC) is an important adjunct for the assessment of adrenal function. In this study, we have analysed cortisol concentrations in urine samples by gas chromatography-mass spectrometry (GC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and two immunoassays. The results were compared with GC-MS. The interference of cortisol ring-A metabolites in immunoassays was also assessed. Methods: The GC-MS technique involved solvent extraction, LH-20 clean-up and derivatization. Only solid-phase extraction procedure was used for LC-MS/MS. The samples were analysed in positive electro-spray ionization mode, monitoring the transitions for cortisol and deuterated-cortisol at m/z 363.3 > 121.2 and m/z 365.3 > 122.2, respectively. Immunoassays were performed according to the manufacturer's instructions. Results: When compared with GC-MS results both immunoassays (Coat-A-Count; approximately 1.9-fold, Centaur; approximately 1.6-fold) overestimated UFC concentrations. Cortisol ring-A dihydro- and tetrahydrometabolites contribute significantly to this overestimation. There was no interference by these metabolites in either GC-MS or LC-MS/MS methods. The sensitivity of the LC-MS/MS procedure was 2 nmol/L and the intra- and inter-assay variations were <5% in each quality-control sample. The comparison of the UFC results achieved by assaying the study samples with GC-MS and LC-MS/MS indicated that the agreement between the two methods was excellent (LC-MS/MS = 1.0036GC-MS ? 0.0841; r2 = 0.9937). Conclusions: The interference of cortisol ring-A metabolites in immunoassays contribute to overestimation of UFC concentrations. The LC-MS/MS procedure had the sensitivity, specificity, linearity, precision and accuracy for the determination of UFC concentrations. The method is suitable for routine use provided that method-dependant reference values are established.
  10. Happy to pay in advance for one when/if you get a pool of us that want a batch? Sorry you got stuck with some too.
  11. I tried to get one of the magnets. I wasn't fast enough I guess. If you get another batch of those, I'd bet interested!
  12. I think the biggest disservice doctors do is assume that each disease/condition is acting in a vacuum or that because you have one condition you can't possibly have another. It's like assuming you're brakes can't be bad on your car because you need new headlights. Or as I'm learning...that if one thing goes wrong in your emissions system there's a huge and expensive cascade effect through the entire system and fixing one problem can unmask another problem. I don't know the Medicare answer but I'd think since it's Federal there'd be some crossover? Anyone else with more knowledge that can chime in?
  13. Phaeochromocytoma combined with subclinical Cushing's syndrome and pituitary microadenoma GF Yaylali, F Akin, M Bastemir, YT Yaylali, and A Ozden Clin Invest Med, January 1, 2008; 31(3): E176-81 Pamukkale University, School of Medicine, Department of Endocrinology and Metabolic Diseases, Denizli, Turkey. guzinf@gmail.com OBJECTIVES: Phaeochromocytoma (PHEO) occasionally associates with pathological lesions of the adrenal cortex. The coexistence of PHEO and pre-clinical Cushing's syndrome (PCS) of the same adrenal gland has rarely been reported. We report a case of PHEO and PCS originating from the same adrenal gland and discuss the peculiar diagnostic aspects of this entity. CLINICAL PRESENTATION: A 64 yr old man was hospitalized to evaluate the right adrenal mass which was discovered incidentally by ultrasonography. He had a history of type 2 diabetes mellitus and hyperlipidemia. Blood pressure measurements were all normal during his hospital stay. Laboratory examination showed: urinary catecholamines were markedly increased. HbA1C of 14.3 %, midnight cortisol of 11(microg/dL), cortisol was not suppressed after the overnight 1 mg oral dexamethasone suppression test (DST): 3.42(microg/dL), 24 hr free cortisol in the urine : 213 microg/day (10-100), cortisol levels were suppressed more than 50% with 8 mg of dexamethasone. CT scan of the adrenal glands showed a 6 cm well encapsulated right adrenal mass together with a clearly normal left adrenal gland. MRI investigation of the sella turcica revealed a pituitary microadenoma on the right side of the adenohypophysis He was treated with alpha and subsequent beta blockers after the diagnosis of PHEO and PCS was made. Right adrenalectomy was performed. The pathology showed typical PHEO with adrenocortical hyperplasia. VMA, metanefrin and free cortisol levels were normalized one month after surgery. CONCLUSION: The present report is a rare case of PHEO combined with PCS in the same adrenal gland. Publication Type: * Journal article PMID: 18544281
  14. I tried to find the complete article but wasn't able to access it. This is the abstract...(and based on what I read in the abstract I'm still looking for the punchline. Did I miss the big story in it?) Lower Growth Hormone and Higher Cortisol are Associated with Greater Visceral Adiposity, Intramyocellular Lipids and Insulin Resistance in Overweight Girls Madhusmita Misra1*, Miriam Bredella2, Patrika Tsai3, Nara Mendes3, Karen K. Miller3, and Anne Klibanski3 1 Pediatric Endocrine Unit, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts, United States 2 Radiology, Massachusetts General Hospital, Boston, Massachusetts, United States 3 Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States * To whom correspondence should be addressed. E-mail: mmisra@partners.org. Background: Although overweight adolescents have markedly altered body composition, insulin sensitivity and lipids, hormonal associations with these parameters have not been well characterized. Growth hormone (GH) deficiency and hypercortisolemia predispose to abdominal adiposity and insulin resistance, and GH secretion is decreased in obese adults. Objective: We hypothesized that low peak GH on the GHRH-arginine stimulation test, and high cortisol in overweight adolescents would be associated with higher regional fat, insulin resistance and lipids. Design/Methods: We examined the following in 15 overweight girls and 15 bone-age-matched controls 12-18 years: (i) body composition using DXA and MR [visceral and subcutaneous adipose tissue (VAT and SAT) at L 4-5, and soleus-intramyocellular lipid (IMCL) (1H-MRS)], (ii) peak GH on the GHRH-arginine stimulation test, (iii) mean overnight GH and cortisol, (iv) 24-hour urine free cortisol (UFC), (v) fasting lipids, and (vi) an OGTT. Stepwise regression was the major tool employed to determine relationships between measured parameters. Results: Log peak GH on the GHRH-arginine test was lower (p=0.03) and log UFC higher (p=0.02) in overweight girls. Log mean cortisol (overnight sampling) was associated positively with SAT, and with BMI-SDS accounted for 92% of its variability, whereas log peak GH and BMI-SDS accounted for 88% of VAT variability, and log peak GH for 34% of the IMCL variability. Log mean cortisol was independently associated with log HOMA-IR, LDL and HDL and explained 49- 59% of the variability. Conclusions: Lower peak GH and higher UFC in overweight girls are associated with visceral adiposity, insulin resistance and lipids.
  15. Thanks! Yeah...I'm so tired of the if/then and multiple choice answers. I'd be okay with an essay answer at this point. It doesn't have to be A, B, C, or D...it could be all of the above or none of the above...or not even be in the book!
  16. Certainly good to see that options for people who are looking at no options are being explored. I'd have to think long and hard about the choice between a BLA and a medication that could potentially suppress hormone production if those were the only 2 options I was facing.
  17. Ovarian Hyperstimulation Syndrome Caused by an FSH-Secreting Pituitary Adenoma Odelia Cooper; Jordan L Geller; Shlomo Melmed Nat Clin Pract Endocrinol Metab. 2008;4(4):234-238. ?2008 Nature Publishing Group Posted 05/21/2008 Summary Background: A 40-year-old woman presented with galactorrhea and oligomenorrhea. She had a history of multiple ovarian cysts and pelvic pain. Investigations: Laboratory evaluation included measurements of the levels of estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, thyroid-stimulating hormone, free endogenous T4, the glycoprotein hormone α subunit, cortisol, adrenocorticotropic hormone, and insulin-like growth factor I. Radiological studies included MRI of the pituitary. Diagnosis: Ovarian hyperstimulation syndrome caused by a pituitary adenoma, secreting follicle-stimulating hormone. Management: The patient underwent trans-sphenoidal resection of the adenoma, with subsequent normalization of hormonal values and symptoms. The Case A 40-year-old woman presented in 2006 with a 15-year history of bilateral galactorrhea. She has never been pregnant and had initially presented at the age of 25 years with menometrorraghia (dysfunctional uterine bleeding) and bilateral galactorrhea, while being on oral contraceptives. At that time investigations revealed the presence of benign luteinized follicular cysts, which were resected laparoscopically. Her symptoms then temporarily abated, but recurred with re-growth of ovarian cysts and with features of the ovarian hyperstimulation syndrome (OHSS) including pelvic pain and enlarged, multicystic ovaries, which required three separate operations over the following 5 years. The patient was referred for endocrinological evaluation in 2006, because she had persistent galactorrhea. At this time, she reported having had a normal adrenarche and puberty, and she denied suffering from headaches, visual disturbances, weight or body habitus changes, polyuria, hirsutism or acne. Her history revealed that she was receiving the oral contraceptive pill. On physical examination, she was found to have bilateral galactorrhea. Biochemical testing demonstrated a negative pregnancy test, prolactin levels of 3,000 pmol/l (reference range 165-1,009 pmol/l), follicle-stimulating hormone (FSH) levels of 19.2 IU/l (reference range 4-13 IU/l), luteinizing hormone (LH) levels of 0.6 IU/l (reference range 1-18 IU/l), estradiol levels of 3,851.0 pmol/l (reference value <1,094.0 pmol/l), adrenocorticotropic hormone levels of 2.9 pmol/l (reference range 1.1-5.9 pmol/l), 0800 h cortisol levels of 510.4 nmol/l (reference range 165.5-634.6 nmol/l), glycoprotein hormone α subunit levels of 0.8 ?g/l (reference range 0.04-0.38 ?g/l), TSH levels of 3.3 mIU/l (reference range 0.39-4.6 mIU/l), free endogenous T4 levels of 11.6 pmol/l (reference range 10.3-34.7 pmol/l), and insulin-like growth factor I levels of 33.7 nmol/l (reference range 18.1-53.7 nmol/l). MRI of the pituitary gland revealed a 16 x 27 x 22 mm pituitary adenoma with suprasellar extension, elevation and compression of the optic chiasm, and extension to the right cavernous sinus (Figure 1). The patient underwent trans-sphenoidal resection of the pituitary mass. Immunohistochemical staining of the pituitary adenoma specimen was positive for α subunit, FSH? subunit and LH? subunit; staining was negative for growth hormone, prolactin, adrenocorticotropic hormone and for TSH. The Ki-67 proliferative index, measuring the growth fraction of tumor cells, was low (1%) and almost no cells showing overexpression of p53 protein were detected. These findings generally suggests a low tumor grade and a good prognosis. The patient was diagnosed as harboring a gonadotrope cell adenoma with secondary ovarian hyperstimulation. Postoperatively, galactorrhea resolved, and normal menses resumed. Anterior pituitary hormone reserve was intact. Discussion of Diagnosis This case typifies the presentation of OHSS in the face of an FSH-secreting adenoma. OHSS comprises extravasation of fluid into the peritoneal cavity, with consequent ascites, hemoconcentration, and electrolyte abnormalities. When OHSS is caused by an FSH-secreting adenoma, FSH levels are usually elevated, LH is suppressed, and estradiol levels are elevated up to 80 times the normal levels. Women suffering from OHSS usually develop enlarged multicystic ovaries associated with abdominal pain. The detection of elevated prolactin levels then triggers the ordering of a pituitary MRI, which will reveal the presence of a pituitary adenoma. In general, women with FSH-secreting tumors are asymptomatic, and often FSH levels are only marginally above the normal range for reproductive-age women. Gonadotropin-secreting adenomas are more common in postmenopausal women, who are relatively insensitive to ovarian hyperstimulation.[1] Gonadotropinomas account for 15-40% of all pituitary tumors. More than 80% of clinically nonfunctioning pituitary adenomas are estimated to be gonadotrope-derived, accounting for approximately half of all macroadenomas. These adenomas often arise in middle-aged men, who may have low testosterone levels with high LH and FSH levels, suggesting a diagnosis of primary hypogonadism. There are also a few reports of male gonadotropinomas leading to elevated testosterone levels resulting in an increased sperm count, and, in addition, there is a case report of a 7-year-old boy who developed precocious puberty as a consequence of a gonadotropin-secreting adenoma.[2,3] Women with intact gonadotrope adenomas and supra-normal FSH levels are generally not recognized as exhibiting a syndrome, because many are over 45 years of age with ovaries devoid of pre-antral follicles, and are insensitive to the action of FSH.[4] These gonadotrope adenomas are, therefore, more difficult to diagnose in women who are perimenopausal or postmenopausal.[5] In women, gonadotropinomas should also be considered if there is a history of headaches or visual changes. Measurements of basal FSH, LH, and α subunit levels may aid the diagnosis, as supra-normal α subunit levels with intact LH and FSH levels, or with disproportionate FSH and LH levels, suggest the presence of a gonadotropinoma, especially when the hormone subunits are induced by a TRH (TSH-releasing hormone) stimulation test. Administration of TRH rarely enhances gonadotropin or gonadotropin subunit secretion in healthy individuals, whereas it can enhance subunit secretion in up to 70% of patients with gonadotropinomas. Although LH? is the gonadotropin subunit most sensitive to increase on administration of TRH, there is currently no standard commercial assay for measuring the LH? subunit, making this protein impractical for routine use.[5] Clinical and biological behavior of gonadotropinomas has been gleaned from in vitro studies and from limited case reports and case series. Gonadotropinomas exhibit variable degrees of differentiation. Only up to 15% of tumor cells -- grouped in small islets around blood vessels in the tumor parenchyma -- show immunohistochemical staining (of variable intensity), which could explain the low levels of circulating hormone concentrations. Nonfunctioning gonadotropinomas are mainly composed of tumor cells with negative immunostaining for all pituitary hormone antibodies, but these tumor cells usually stain positively for the DAX-1 (Nuclear receptor subfamily 0 group B member 1) protein, which regulates gonadotrope differentiation.[5] The bioactivity and concentration of baseline serum FSH are higher in patients with adenomas than in controls. In addition, bioactive and immunoreactive FSH levels increase in response to the administration of TRH in patients with adenomas. The cellular machinery for biosynthesis and processing of FSH is intact, and functional FSH is secreted despite aberrant tumor growth.[6] It should, however, be mentioned that the unassociated LH? and FSH? subunits exhibit no intrinsic biological activity and that formation of a heterodimer with the α subunit is essential for biological activity. As 70-100% of nonfunctioning adenomas secrete free subunits, these tumors usually show no biological activity.[7] In a subject with an intact pituitary gland, one would expect that high estradiol levels would suppress gonadotropin-releasing hormone (GnRH) and, therefore, suppress gonadotropin secretion. In gonadotrope adenomas, however, the normal feedback system is impaired, thereby permitting the presence of persistently elevated FSH and estradiol levels, which then leads to the symptoms and signs of OHSS. Clinical behavior of gonadotropinomas has been described in a number of case series, including an analysis of 100 patients with gonadotropin-positive pituitary adenomas reported between 1976 and 1992.[8] In this report, gonadotropin levels were found to be inappropriately low compared with the expected levels in postmenopausal women.[8] LH concentrations were elevated in 36% of males, with 9% showing LH hypersecretion (defined as more than a two-fold increase above the upper limit of normal). FSH levels were elevated in 42% of males, with FSH hypersecretion reported in 19%. Levels of α subunit were high in only 1 of 29 patients. In other case series, however, α subunit levels were elevated in 15-32% of patients.[9-11] Hypogonadism was diagnosed biochemically in 78% of males.[8] These patients presented with mass effect symptoms including loss of vision, symptoms of hypopituitarism, and headaches.[8] On electron microscopy, gonadotrope adenomas showed a gender-related ultrastructural dimorphism. In men, gonadotrope adenomas tend to have small cells with decreased cytoplasmic volume densities of endoplasmic reticulum and Golgi membranes, and with variable numbers of secretory granules. On the other hand, in women gonadotrope adenomas have a well-developed endoplasmic reticulum, a 'honeycomb' Golgi complex and sparse, small secretory granules. Using this distinction, 45% of the adenomas in this series were structurally classified as 'male' gonadotrope adenomas whereas 9% were 'female' adenomas.[8] Hypersecretion of gonadotropins and their subunits rarely leads to a defined clinical syndrome, unlike syndromes associated with prolactin or growth hormone hypersecretion. Consequently, most gonadotropinomas have, heretofore, been classified as nonfunctioning or 'null cell' adenomas. It is known, however, that gonadotropinomas often secrete α subunit, FSH and FSH? subunit as well as LH and LH? subunit. In fact, the 2004 WHO classification of pituitary tumors places gonadotrope adenomas in their own class, as it has now become clear that gonadotrope cells of the anterior pituitary pursue a pathway of differentiation distinct from other tropic hormone cells. Unlike 'null cell' adenomas, gonadotropinomas express the nuclear receptor steroidogenic factor-1 almost exclusively in cells that produce gonadotropin ? subunits; moreover, this factor has been shown to regulate glycoprotein hormone α subunit gene expression in pituitary gonadotrope cells.[12] Patients may present with symptoms of excess gonadotropin secretion leading to the syndrome of ovarian hyperstimulation. The pathogenesis of this syndrome has been explored in an animal model in which transgenic mice with pituitary-directed hypersecretion of LH developed multicystic ovaries. These mice had an increased pituitary size and showed proliferation of Pit-1 (pituitary-specific positive transcription factor 1)-positive cells that culminated in the appearance of functional pituitary adenomas. It is thought that LH could be an extrinsic factor acting through the ovary leading to the formation of functional pituitary adenomas.[13] OHSS has been reported in patients aged 10-39 years, with pituitary tumors varying in size from 8 mm diameter to huge invasive adenomas. As in the case presented here, premenopausal women with FSH-secreting tumors may harbor a clinically functioning adenoma, manifesting with enlarged multicystic ovaries and with abdominal pain. Similar cases in the literature are summarized in Supplementary Tables 1, 2, 3. Differential Diagnosis OHSS can occur in association with other disease states. Patients with polycystic ovary syndrome who become pregnant are at risk of OHSS as they have multiple partially stimulated antral follicles, which can over-respond to exogenous gonadotropins as reported during assisted reproductive treatment. OHSS has also been reported in association with primary hypothyroidism, possibly caused by TSH-mediated stimulation of the FSH receptor or by enhanced TRH production stimulating gonadotropin release. In addition, a single patient with bilateral granulosa cell tumors has been reported to have developed OHSS.[14] Treatment and Management Surgical resection is the definitive and primary therapy for OHSS due to gonadotropin-secreting adenomas. Surgery results in normalization of gonadotropin and estradiol levels. Menstrual cycles resume and the ovaries revert to normal size with cyst remission. In those with recurrent tumors, radiation therapy may be required. Medical therapies are generally not effective. In theory, one possible medical treatment would be the administration of a GnRH analog which would decrease FSH levels, thereby leading to resolution of OHSS; however, reports have actually shown a paradoxical increase in gonadotropin secretion in response to this treatment,[4,15-20] and in one case OHSS was induced after initiation of GnRH therapy with dramatic increases in FSH and estradiol levels.[21] There are three reports of patients with OHSS who were initially treated medically. These patients presented with oligomenorrhea, abdominal distension, and enlarged multicystic ovaries. Estradiol levels were as high as 6,755 pmol/l, with elevated prolactin and FSH levels and suppressed LH levels. The three patients were treated with a dopamine agonist and two of the patients also received medroxyprogesterone. Ovarian volumes and hormonal values normalized. Eventually, however, the adenomas continued to grow and were resected, showing positive immunostaining for LH in two cases and for FSH in one case.[15,22] After resection of a pituitary adenoma, patients are monitored annually with MRI, looking for evidence of a possible recurrence. Patients should also undergo hormonal testing 3 months after surgery to assess whether hypopituitarism is present. If there is evidence of a deficiency of any of the hormones of the pituitary axis, hormonal replacement therapy is initiated. Conclusions We present a case of a woman who developed OHSS due to an FSH-secreting pituitary adenoma. This syndrome comprises enlarged, multicystic ovaries, oligomenorrhea or amenorrhea, elevated estradiol levels and, usually, elevated serum FSH levels. After resection of the pituitary adenoma, the endocrine profile and symptoms revert to normal. Our case brings to light two instructive points. Firstly, contrary to the assumption that gonadotrope adenomas are clinically nonfunctioning adenomas, FSH-secreting adenomas may in fact be functional, leading to hypersecretory symptoms as in the development of OHSS. Secondly, when clinicians encounter patients presenting with symptoms of abdominal pain, abnormal menses and multicystic ovaries, they should measure estradiol and gonadotropin levels to exclude OHSS caused by a pituitary adenoma. In our case, the patient had a 15-year history of such symptoms but had not undergone an endocrine work-up, which could have revealed the presence of a pituitary adenoma during that period. Clinical awareness and an appropriate endocrine work-up facilitate early diagnosis and treatment of this syndrome, thereby avoiding multiple therapeutic procedures for ovarian cysts and ultimately also restoring fertility. CLICK HERE for subscription information about this journal. References 1. Roberts JE et al. (2005) Spontaneous ovarian hyperstimulation caused by a follicle-stimulating hormone-secreting pituitary adenoma. Fertil Steril 83: 208-210. 2. Zarate A et al. (1986) Gonadotropin-secreting pituitary adenoma with concomitant hypersecretion of testosterone and elevated sperm count. Treatment with LRH agonist. Acta Endocrinol 113: 29-34. 3. Ambrosi B et al. (1990) Precocious puberty in a boy with a PRL-, LH- and FSH-secreting pituitary tumor: hormonal and immunocytochemical studies. Acta Endocrinol 122: 569-576. 4. Pentz-Vidovic I et al. (2000) Evolution of clinical symptoms in a young woman with a recurrent gonadotroph adenoma causing ovarian hyperstimulation. Eur J Endocrinol 143: 607-614. 5. Chaidarun SS and Klibanski A (2002) Gonadotropinomas. Semin Reprod Med 20: 339-348. 6. Galway AB et al. (1990) Gonadotroph adenomas in men produce biologically active follicle-stimulating hormone. J Clin Endocrinol Metab 71: 907-912. 7. Melmed S (2002) The Pituitary. Cambridge: Blackwell Science 8. Young W et al. (1996) Gonadotroph adenoma of the pituitary gland: a clinicopathologic analysis of 100 cases. Mayo Clin Proc 71: 649-656. 9. Beck-Peccoz P et al. (1992) Glycoprotein hormone α-subunit in pituitary adenomas. Trends Endocrinol Metab 3: 41-45. 10. Oppenheim DS et al. (1990) Prevalence of α-subunit hypersecretion in patients with pituitary tumors: clinically nonfunctioning and somatotroph adenomas. J Clin Endocrinol Metab 70: 859-864. 11. Nobels FR et al. (1993) A comparison between the diagnostic value of gonadotropins, α subunit, and chromogranin-A and their response to thyrotropin-releasing hormone in clinically nonfunctioning, α subunit-secreting, and gonadotroph pituitary adenomas. J Clin Endocrinol Metab 77: 784-789. 12. Asa SL et al. (1996) The transcription activator steroidogenic factor-1 is preferentially expressed in the human pituitary gonadotroph. J Clin Endocrinol Metab 81: 2165-2170. 13. Mohammad HP et al. (2003) Targeted overexpression of luteinizing hormone causes ovary-dependent functional adenomas restricted to cells of the Pit-1 lineage. Endocrinology 144: 4626-4636. 14. Segal R et al. (1995) Clinical review of adult granulosa cell tumors of the ovary. Gynecol Oncol 56: 338-344. 15. Murata Y et al. (2003) Successful pregnancy after bromocriptine therapy in an anovulatory woman complicated by follicle-stimulating hormone-producing plurihormonal pituitary microadenoma. J Clin Endocrinol Metab 88: 1988-1993. 16. Christin-Maitre S et al. (1998) A spontaneous and severe hyperstimulation of the ovaries revealing a gonadotroph adenoma. J Clin Endocrinol Metab 83: 3450-3453. 17. Maruyama T et al. (2005) Follicle stimulating hormone-secreting pituitary microadenoma with fluctuating levels of ovarian hyperstimulation. Obstet Gynecol 105: 1215-1218. 18. Kihara M et al. (2006) Ovarian hyperstimulation caused by gonadotroph cell adenoma: a case report and review of the literature. Gynecol Endocrinol 22: 110-113. 19. Berezin M et al. (1984) Reduction of follicle-stimulating hormone (FSH) secretion in FSH-producing pituitary adenoma by bromocriptine. J Clin Endocrinol Metab 59: 1220-1223. 20. Yamakita N et al. (1999) Reduction of plasma gonadotropin levels and pituitary tumor size by treatment with bromocriptine in a patient with gonadotropinoma. Intern Med 38: 266-271. 21. Castelbaum AJ et al. (2002) Exacerbation of ovarian hyperstimulation by leuprolide reveals a gonadotroph adenoma. Fertil Steril 78: 1311-1313. 22. Knoepfelmacher M et al. (2006) Effectiveness of treating ovarian hyperstimulation syndrome with cabergoline in two patients with gonadotropin-producing pituitary adenomas. Fertil Steril 86: e15-e18. Acknowledgements Consent for the publication of Figure 1 was obtained from the patient. Funding Information This work was supported by NIH grants T32 DK007770-06A2 and CA75979. Reprint Address Shlomo Melmed, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, CA 90048. E-mail: melmed@csmc.edu . Odelia Cooper, Jordan L Geller, Shlomo Melmed, Cedars-Sinai Medical Center, Los Angeles, CA
  18. Here's the official link from the news report NIH Launches Undiagnosed Diseases Program For Immediate Release Monday, May 19, 2008 Contact: Raymond MacDougall NHGRI 301-402-0911 Sara Byars NIH Clinical Center 301-496-2563 Kelli Marciel Office of the Director, Office of Rare Diseases 301-496-4819 NIH Launches Undiagnosed Diseases Program Clinical Researchers to Tackle the Most Puzzling Medical Cases The National Institutes of Health (NIH) today announced a new clinical research program that will aim to provide answers to patients with mysterious conditions that have long eluded diagnosis. Called the Undiagnosed Diseases Program, the trans-NIH initiative will focus on the most puzzling medical cases referred to the NIH Clinical Center in Bethesda, Md., by physicians across the nation. "A small number of patients suffer from symptoms that do not correspond to known conditions, making their care and treatment extraordinarily difficult. However, the history of biomedical research has taught us that careful study of baffling cases can provide new insights into the mechanisms of disease ? both rare and common," said NIH Director Elias A. Zerhouni, M.D., who has made a point during his six-year tenure at NIH of encouraging trans-NIH initiatives. "The goal of NIH?s Undiagnosed Diseases Program is two-pronged: to improve disease management for individual patients and to advance medical knowledge in general." The new program, which got under way over the past month, is the culmination of efforts by William A. Gahl, M.D., Ph.D., clinical director at the National Human Genome Research Institute (NHGRI), part of the NIH; John I. Gallin, M.D., director of the NIH Clinical Center; and Stephen Groft, Pharm.D., director of the NIH Office of Rare Diseases (ORD). With the program infrastructure now in place, the program is ready to accept patients, the first of which is expected to be seen in July 2008. "The NIH Clinical Center, the nation?s clinical research hospital, provides an extraordinary environment for excellence in both patient care and collaborative clinical investigation," said Dr. Gallin. "This new program will capitalize on a rich set of skills already at the Clinical Center to "help patients with unusual medical conditions. These patients often partner with us in clinical research to identify new diseases or new treatment." To evaluate each patient enrolled in the new program, NIH will enlist the expertise of more than 25 of its senior attending physicians, whose specialties include endocrinology, immunology, oncology, dermatology, dentistry, cardiology and genetics. Dr. Gahl, who is an expert on rare genetic diseases, will serve as director of the new program. "We have developed a stringent referral process to ensure this program deals with those cases that have truly confounded medical experts," Dr. Gahl said. "We will be very selective when it comes to patient eligibility. Our focus is strictly on conditions that have not been diagnosed." To be considered for this NIH pilot program, a patient must be referred by a physician and provide all medical records and diagnostic test results requested by NIH. Patients who meet the program?s criteria ? as many as 100 each year ? will then be asked to undergo additional evaluation during a visit to the NIH Clinical Center that may take up to a week. Two nurse practitioners will manage patient recruitment and logistics for the new program, which will utilize existing facilities and staff already at the NIH Clinical Center, NHGRI and ORD. Funding for the program includes $280,000 per year from the ORD. In organizing the Undiagnosed Diseases Program, NIH has reached out to patient advocacy groups that often serve as a source of information and support for people struggling with mysterious ailments."We hope to build upon our strong working relationships with many patient advocacy groups. These organizations provide a crucial link in our nation?s efforts to improve human health through biomedical research," said Dr. Groft." We hope that this new partnership of NIH researchers, advocacy groups and patients will give hope for many Americans who now face troubling medical symptoms with no clear diagnosis." For more information about the Undiagnosed Diseases Program, go to: http://rarediseases.info.nih.gov/Undiagnosed. Physicians and patients with specific inquiries may call the NIH Clinical Center clinical information research line, at 1-866-444-8806. The NIH Clinical Center (CC) is the clinical research hospital for the National Institutes of Health. Through clinical research, physician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. For more information, visit http://clinicalcenter.nih.gov. The NIH Office of Rare Diseases stimulates and coordinates research on rare diseases and supports research to respond to the needs of patients, health care providers and the research communities involved in the care, treatment, and evaluation of products for the prevention, diagnosis, or treatment of these conditions. For more information about ORD and its programs, visit rarediseases.info.nih.gov. The Office of the Director, the central office at NIH, is responsible for setting policy for NIH, which includes 27 Institutes and Centers. This involves planning, managing, and coordinating the programs and activities of all NIH components. The Office of the Director also includes program offices which are responsible for stimulating specific areas of research throughout NIH. Additional information is available at http://www.nih.gov/icd/od/index.htm. NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site, www.genome.gov. The National Institutes of Health (NIH) ? The Nation's Medical Research Agency ? includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. NIH logo Home > News & Events E-mail this page Subscribe to receive future NIH news releases.
  19. Not yet...and I would tend to agree with you. Would explain why our tumors are different among other things wouldn't it? (and I toot my scooter horn and taken no offense by it so don't worry )..and as a side note...had to bite my tongue not to laugh as my cell phone went off in the doctor's office today playing..."I'm only human."
  20. I hope it helps and that you get in by some sort of criteria. My husband is convinced they will find that there is some kind of genetic disease that causes all these mutations in my family some day...but it'll be too late for me because we have no idea what to even to look for at this point.
  21. Feds to Offer Free Health Care to People With Very Rare Diseases They're the cold cases of medicine, patients with diseases so rare and mysterious that they've eluded diagnosis for years. The National Institutes of Health is seeking those patients ? and ones who qualify could get some free care at the government's top research hospital as scientists study why they're sick. "These patients are to a certain extent abandoned by the medical profession because a brick wall has been hit," said Dr. William Gahl, who helped develop the NIH's new Undiagnosed Diseases Program. "We're trying to remove some of that." The pilot program, announced Monday, can only recruit about 100 patients a year. But federal health officials hope that unraveling some of these super-rare diseases in turn will provide clues to more common illnesses. "We believe this is not only a service to be rendered, but also knowledge to be gained," said NIH Director Dr. Elias Zerhouni. About 10,000 new patients a year sign up for roughly 1,500 different research studies, many of them for rare diseases, at the NIH's Bethesda, Md., hospital, the innocuously named Clinical Center. The new mystery-disease program is aimed at people with the rarest of the rare diseases ? even those with truly brand-new ailments ? who otherwise would be turned away because there are no studies, yet, for their conditions or a researcher specifically tracking their symptoms. It doesn't promise a diagnosis, but the chance to be reevaluated by a team of renowned specialists. Amanda Young of Conyers, Ga., illustrates patient frustration. By age 3 1/2, she had suffered repeated lifethreatening infections that left doctor after doctor baffled. At 8, a scratch turned gangrenous, requiring her leg to be amputated. Yet under the microscope, her immune system seemed normal except for an unexplained low white blood cell count. In 1990, not long after that amputation, her desperate parents brought her to NIH, where the hospital director "made us a promise," Young recalled. "He told us he would never give up on me." It took until 2003, but Young got a phone call: "My disease finally had a name." Gene research had uncovered a previously unknown immune-system pathway ? showing NIH's Dr. John Gallin that Young harbors an extremely rare mutation, named IRAK4 deficiency, that means she lacks a protein key for that pathway to work. There's no treatment yet. But Young, now 26, continues to volunteer for research in hopes of one. To be considered for the new program, a doctor must refer a mystery patient to the NIH and send all medical files for evaluation. Accepted patients will undergo up to a week's additional testing at the Clinical Center, for free. For more information, see http://rarediseases.info.nih.gov/undiagnosed or call 1-866-444-8806
  22. I ran across this great cookie cutter while I was looking for a gift for a friend. It occurred to me that those that set up booths, etc might be interested in another way to bring the crowds over...or just to pass out at work on April 8th or whenever you feel the urge to share the message...anyway...this is really neat! cookie cutter
  23. Does a failure to normalize diurnal glucocorticoids negate the benefits of exercise training? Kevyn Mejia-Hernandez, Jon E. Campbell and Michael C. Riddell School of Kinesiology and Health Science, York University, Toronto, Canada ABSTRACT Glucocorticoids (GCs) are released by the hypothalamic-pituitary-adrenal (HPA) axis in response to a variety of stressors. Although acute elevations of GCs are beneficial, prolonged exposure has significant and detrimental metabolic consequences, most notably seen in Cushing's syndrome. Here, we created an animal model of Cushing's syndrome and investigated the impact of exercise training on various metabolic parameters. Male Sprague-Dawley rats were divided into exercise and sedentary groups and further subdivided into control (SHAM) and corticosterone (CORT) groups. Exercising animals had access to running wheels for 6 weeks, while sedentary animals remained in standard cages. A 300mg corticosterone pellet was implanted subcutaneously in CORT rats while SHAM rats received a wax pellet. Within 1 week, both sedentary and exercising CORT rats demonstrated a {approx}15-and 1.7-fold elevation in nadir and peak GCs levels respectively, resulting in an abolished diurnal pattern. Relative to body weight, sedentary CORT animals had more epididymal fat when compared to sedentary controls. Conversely, exercise CORT rats had epididymal fat content comparable to that of exercise SHAM animals. This study proposes a new animal model of Cushing's syndrome and reveals that regular exercise attenuates the accumulation of visceral fat mass in this animal model. This study was funded by NSERC.
  24. I saw that yesterday and have been digging around ever since trying to find the actual guidelines. I think they've got them under lock and key on an endo only website. Sigh...Glad to hear they've updated the guidelines though!
  25. The Role of Sex Steroids in Controlling Pubertal Growth R. J. Perry; C. Farquharson; S. F. Ahmed Clin Endocrinol. 2008;68(1):4-15. ?2008 Blackwell Publishing Posted 03/03/2008 Summary and Introduction Summary Longitudinal growth, which is primarily due to chondrocytic activity at the level of the epiphyseal growth plate, is influenced by many hormones and growth factors in an endocrine and paracrine manner. Their influence is even more complex during the accelerated growth period of puberty that accounts for about 20% of final adult height. Although abnormalities of growth during puberty are very common, the underlying mechanisms that govern the beginning and cessation of pubertal growth at the level of the growth plate are poorly understood. Sex steroids play a crucial role in pubertal growth both at the systemic level via the GH/IGF-1 axis and at the local level of the epiphyseal growth plate. In both sexes it is now accepted that oestrogen is the critical hormone in controlling growth plate acceleration and fusion. This paper reviews the mechanisms that influence pubertal growth and the problems that are associated with disorders of gonadal function. Introduction Longitudinal growth is a complex process regulated by several hormonal and genetic factors, environment and nutrition. Among these, sex steroids are of crucial importance and the most obvious demonstration of their effect on human growth is the initiation, maintenance and decline of the pubertal growth spurt. The effect of sex steroids on growth can be studied in detail at two levels: the systemic level and the local level of the epiphyseal growth plate. In this review, we summarize current knowledge about the mechanisms by which sex steroids influence growth before dealing specifically with the growth problems associated with gonadal disorders. Systemic Effects of Sex Steroids on GH-IGF-I Axis The striking increase in growth velocity (GV) during puberty is under complex endocrine control. GH increases growth at puberty through the stimulation of insulin-like growth factor-I (IGF-I) production. During puberty the pulsatile secretion of GH increases (1.5 to 3-fold) along with a greater than three-fold increase in serum IGF-I levels. Peak IGF-I levels occur at 14.5 years in girls and 1 year later in boys.[1] The rise in mean 24-h GH levels results from an increase in the maximal GH secretory rate and also in the mass of GH per secretory burst.[2,3] The increase in GH secretion during puberty shows a sexually dimorphic pattern that parallels the change in GV. In girls, an increase in circulating GH is seen relatively early in puberty at Tanner breast Stage 2 (B2) with peak levels coinciding with B3-4. In boys, this increase in GH is seen later with the peak occurring at Tanner genital Stage 4 (G4).[4] After secondary sexual development is complete, GH and IGF-I levels fall to prepubertal levels in both sexes. The secretion of GH is mediated by two hypothalamic hormones: growth hormone releasing hormone (GHRH) and somatostatin. GHRH has a stimulatory effect whereas somatostatin has an inhibitory effect. These hypothalamic influences are tightly regulated by an integrated system of neural, metabolic and hormonal factors.[5] In animal studies (principally rodents) sex steroids influence GH synthesis and secretion with effects on both the hypothalamus and anterior pituitary. In the neonatal period, sex steroids influence the number of GHRH neurones which will be present in the adult hypothalamus and also their response to postpubertal steroids.[6] Postpubertally, androgens modify hypothalamic somatostatin synthesis whereas oestrogens modify GHRH synthesis. In addition, both neonatal and postpubertal steroids influence the secretory pulsatility of anterior pituitary hormone release by altering hypothalamic synaptic organization.[6] At the level of the pituitary, sex steroids modify the response of somatotrophs to somatostatin.[6] Androgens Dihydrotestosterone (DHT) and oxandrolone increase GV in boys with delayed puberty without any alteration of serum GH/IGF-I.[7-10] In contrast, testosterone, typically, increases GV in association with an increase in GH/IGF-I.[11] This ability of testosterone to stimulate GH secretion is principally due to its conversion to oestrogen by aromatization. This is supported by a study in pubertal boys who showed a reduction in GH and IGF-I when treated with tamoxifen [an oestrogen receptor (ER) blocker].[12] The nonaromatizable androgens (DHT and oxandrolone) increase GV independent of GH/IGF-I suggesting that "pure androgens" may stimulate growth through other mechanisms, possibly via a direct action on the androgen receptor (AR) within the growth plate cartilage.[13] Oestrogens Oestrogen stimulation of growth is largely dependent on pituitary GH and is mediated via the oestrogen receptors, oestrogen receptor-alpha (ER-α) and oestrogen receptor-beta (ER-?), which are expressed in the anterior pituitary as well as the hypothalamus. GH and oestrogen levels show positive correlations in prepubertal girls and boys.[14,15] Endogenous oestrogen in peri-pubertal children increases GH sensitivity.[16] Oestrogen priming for GH-stimulation testing has been shown to augment GH release in normal adolescents.[17] Furthermore, GH secretion is reduced when oestrogen signalling is blocked.[12,18] This tight relationship between oestrogen and GH status is further demonstrated by the strong correlation between oestrogen and GH concentrations throughout normal female puberty.[19] GH levels are higher in women compared to in men.[20,21] As boys and girls with IGF-I deficiency (Laron syndrome) do not have a discernible pubertal growth spurt,[22] a major part of the stimulation of growth by oestrogen is through the GH-IGF-I axis. The effect of exogenous oestrogen depends on its form. If oestrogen treatment is administered orally (for hormone replacement therapy), large supraphysiological doses are required as oestrogen is actively metabolized by the hepatic cytochrome system. This supraphysiological concentration in the portal circulation perturbs many aspects of hepatic function. The liver is the major site of GH-regulated metabolism and the main source of IGF-I.[23] Oral oestrogen administration leads to increased circulating GH levels and a reduction in IGF-I production. The high oestrogen concentration in the portal circulation impairs hepatic IGF-I production and increases the concentrations of growth hormone binding protein (GHBP) which binds to GH and thereby blunts its action. There is also stimulation of the synthesis of angiotensinogen, clotting factors, lipoproteins and the binding proteins for several steroid hormones. These metabolic sequelae are not seen with transdermal administration.[24] Local Effects of Sex Steroids on the Growth Plate In addition to its systemic effects GH also has a direct action at the level of the growth plate. GH enhances the recruitment of resting zone chondrocytes and local IGF-I production in the growth plate.[25-28] It remains unclear about the contribution of systemic vs. local IGF-I to longitudinal growth. However, they both appear to have an impact on longitudinal growth (in mice at least). The liver-derived IGF-I gene-deleted mouse model (LID) has normal growth but circulating IGF-I levels are only reduced by 75%. When the LID mice were crossed with the acid labile subunit (ALS) gene-deleted mice (ALSKO), the LID/ALSKO mice had a further reduction in circulating IGF-I levels (85-90%) and showed early postnatal growth retardation.[29] But tissue IGF-I may still play a role because the total IGF-I knockout mice show more marked growth retardation. However, basal IGF-I production by growth plate chondrocytes is reported to be minimal.[30,31] Sex Steroids Sex steroids are likely to have a direct action on chondrocytes because the AR and both ER-α and ER-?, have been demonstrated in GP tissue at the mRNA and protein level in several species, including rat, rabbit and human.[13] Androgens The AR has been demonstrated in all layers of the human growth plate at different ages with no significant gender variation.[32-35] Several studies support a direct stimulatory effect of androgens on the growth plate cartilage. In vitro studies have shown that DHT regulates proliferation and differentiation of cultured human epiphyseal chondrocytes, probably by promoting local IGF-I synthesis and increasing IGF-I receptor expression.[36] The sex-specific response of rat costochondral growth zone chondrocytes to testosterone requires the further metabolism of the hormone to DHT and this DHT effect in the male growth plate is maturation-state dependent.[37] Similarly in vivo, a nonspecific ER blocker (Faslodex, Zeneca Pharmaceutical Company, Wilmington, DE) did not prevent the advancement of bone maturation in mice treated with testosterone.[38] Also, direct injections of testosterone into the rat tibial epiphyseal growth plate increased growth plate width without alteration of IGF-I production.[39] Furthermore, DHT stimulates longitudinal bone growth in ovariectomized (OVX) rats[40] and testosterone increases growth plate width in castrated, hypophysectomized male rats.[41] Oestrogens The ERs have been demonstrated in all maturational zones of the human growth plate during development and puberty. However, there is conflicting evidence from in vitro studies on the effect of oestrogen on chondrocyte proliferation and differentiation.[42-49] Some of the discrepancies may be explained by the demonstrated ability of chondrocytes to synthesize oestrogen themselves.[49-51] Activation of the ERs by locally produced oestrogen could minimize or eliminate the effect of exogenous oestrogen. To complicate matters further, oestrogen signalling can occur via genomic or nongenomic pathways. The new oestrogen receptor GPR30 is expressed in the human growth plate and down-regulated during pubertal progression.[52] This new receptor may explain some of the previous "non-genomic" actions of oestrogen. It is a G-protein coupled receptor which is also involved in changes in calcium levels.[53] Furthermore, some of the rapid responses to oestrogen, including activation of protein kinase C, are limited to cells from female animals.[46,54,55] In vivo, oestrogen inhibits chondrocyte cell division in the proliferative zone (PZ) of the rat growth plate.[56-58] The age-related decrease in size of the hypertrophic chondrocytes[59,60] is enhanced by oestrogen.[58] In rats, the withdrawal of oestrogen by OVX stimulates longitudinal bone growth.[61] This increase in bone length is associated with increased chondrocyte proliferation[51] growth plate width[51] and IGF-I production.[40,51] Similarly, in humans, tall girls treated with high-dose oestrogen display a rapid reduction in GV but have only a modest decrease in serum IGF-I suggesting a direct, non-GH-dependent, effect of oestrogen.[62] Moreover, children with precocious puberty (PP) and GH deficiency can have a pubertal growth spurt.[63] Lessons Learned from ER Knockouts in Mouse and Man Meta-analysis of longitudinal bone length in these knockouts has shown that the role played by the oestrogen receptors (ER) in association with bone length may depend on sex and age ( Table 1 and Table 2 ).[64-77] ER-? has an inhibitory effect on longitudinal bone growth in adult female mice only.[65,66,70] It has been hypothesized that this inhibitory action is only seen in the presence of elevated serum oestrogen levels - this is supported by the finding that adult female BERKO (ER-? knockout) mice have the highest serum oestrogen levels[71] during which period the inhibitory effect of ER-? is exclusively seen. Furthermore, female ERKO (ER-α knockout) mice have shorter bones than female DERKO (both ER-α and ER-? absent).[65,66] Both of these strains have markedly elevated serum oestrogen levels due to an inactive feedback loop.[65] Knocking out ER-? does not affect femur length in male mice of any age.[70,71,75] Finally, in the presence of high levels of oestrogen, ER-? induces fusion of the growth plate in older female mice.[66,67] Knocking out ER-α does not have an effect on growth of younger mice but may inhibit growth in the older ones.[64-69,75,76] There is no evidence of sexual dimorphic effects. The patient lacking ER-α (hERKO) carries a mutation at residue 157 in the protein, which would allow the short, 46-kD spliced form of ER-α to be synthesized.[78] This is one possible explanation for discordance in phenotype between mice and man. Growth in Puberty There are at least three distinct phases of postnatal growth. The infantile phase is the first phase with rapid GV during foetal life followed by rapid deceleration up to 3 years of age. The childhood phase follows, which has a slowly decelerating velocity until puberty. The pubertal phase shows acceleration in GV and reaches a peak on average 22 months after initiation. GV then rapidly decreases and ceases.[79] This pubertal growth comprises 15-20% of final height (FH) and precedes fusion of the growth plates. Both the amplitude of the pubertal spurt and peak GV vary negatively with the age of onset of puberty.[79-81] Concordance is shown between the pubertal growth spurt and clinical pubertal development.[79,82,83] The tempo of pubertal growth shows sexual dimorphism. Growth acceleration is usually seen early with peak GV occurring at B2 in 40%, B3 in 30%, B4 in 20% and B1 in 10% of girls.[79] In contrast, there is an acceleration of growth usually during the second year of pubertal development with peak GV occurring at G3 in 60%, G4 in 28%, G2 in 8% and G5 in 4% in boys.[79] This dimorphic pattern may be related to the delay in boys reaching the level of oestrogen required (from aromatization of testosterone). Aromatization is mediated by aromatase (an enzyme of the cytochrome P450 group) whose function is to mediate the conversion of androgens to oestrogens. The pubertal growth spurt is primarily due to increased secretion of the sex steroids, oestrogens and androgens. It has been widely accepted that oestrogen mediates pubertal bone growth in females; however, it has only recently been established that oestrogen, and not testosterone, mediates the same function for males. The growth patterns observed in certain rare syndromes suggest that, in humans, oestrogen is responsible for the initiation of the pubertal growth spurt and closure of the growth plate in both sexes. Inactivating mutations in either the ER-α gene or the aromatase gene in males have resulted in a lack of a pubertal growth spurt, absent epiphyseal closure with resultant tall stature (taller than predicted). The individual with a defective ER-α is unique.[84] He presented with tall stature, normal male sexual maturation, osteoporosis and open epiphyses. Treatment with oestrogen did not produce epiphyseal fusion nor improve his bone mineral density. A similar phenotype was described in a 24-year-old man with congenital aromatase deficiency who had tall stature, a bone age (BA) of 14 years and osteoporosis despite high testosterone levels.[85] Treatment with conjugated oestrogen for 6 months led to fusion of the growth plates and increased bone mineral density.[86] Aromatase deficiency has now been described in others and they all show persistent linear growth in adulthood with open epiphyseal growth plates.[87,88] Although data are limited, it has been reported that they seem to have an absent growth spurt and fusion of the growth plates occurs after treatment with exogenous oestrogen but not with testosterone.[87] 46,XY girls with complete androgen insensitivity syndrome (CAIS) do have a pubertal growth spurt, which tends to occur at a similar age and of similar amplitude to unaffected girls, thus, demonstrating that oestrogen is able to increase GV in the absence of androgens.[89] Pubertal growth is influenced by the amount of body fat. In a longitudinal study of normal children, an additional body mass index (BMI) point (+1 kg) was reported to decrease the growth spurt by a mean of 0.5 cm and 0.9 cm, in girls and boys, respectively. However, FH was not affected due to the growth acceleration observed in childhood.[90] It has been widely accepted that longitudinal growth ceases in late adolescence as a result of epiphyseal fusion, an abrupt event in which growth plate cartilage is replaced by bone tissue. However, careful observation suggests that growth ceases before fusion occurs[91,92] which suggests that fusion is the result of growth cessation.[92,93] The deceleration in longitudinal growth was previously attributed to a systemic mechanism. However, recent evidence indicates that it is caused by a local mechanism within the growth plate. In growth plate-transplantation studies, the growth rate of the transplanted growth plate depended on the age of the donor animal and not on that of the recipient.[94] This intrinsic mechanism has been referred to as "growth plate senescence".[95] The senescent decline in growth rate is mainly due to a decrease in the rate of chondrocyte proliferation in the growth plate.[96] Young rabbits treated with systemic dexamethasone for a 5-week period showed a reduction in longitudinal bone growth.[97] After recovery, their growth plates showed a delay in senescent decline in the growth rate, chondrocyte proliferation rate, growth plate height, PZ and hypertrophic zone (HZ) height.[97] This programmed senescence appears to be a function of proliferation. Oestrogen is reported to accelerate the normal process of growth plate senescence, leading to earlier exhaustion of the growth plate and, as a consequence, earlier fusion.[92] However, this hypothesis was not supported by a recent study of castrated male rabbits[98] in which oestrogen was shown to decrease proliferation in the resting zone (RZ) chondrocytes. This latter study examined younger, male rabbits, which were treated for a shorter period of time (2 weeks compared to 8 weeks) and the plasma oestrogen levels achieved were much lower. Disorders of Puberty that Lead to Growth Disturbance Premature Sexual Maturation This is traditionally defined by the onset of puberty before the age of 8 years in girls or 9 years in boys. The occurrence of menarche before the age of 10 years also indicates sexual precocity. In the USA, these criteria have been reconsidered due to a community-based study of 17 000 girls who showed a trend towards earlier breast development.[99] However, age at menarche is unaltered, suggesting that the tempo of puberty in the early developers may be slower. It has been proposed that the age of 7 years for white girls and 6.5 years for the African American population should be used as a cut-off for defining early puberty.[100] In boys, the cut-off is unchanged. In Europe, the original criteria are still valid as there is no evidence of a recent reduction in age at onset of puberty in either gender.[101] Precocious puberty can be classified as central precocious puberty (CPP) or gonadotrophin-independent precocious puberty (GIPP). CPP involves the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. In GIPP the presence of sex steroids is independent of pituitary gonadotrophin release. Isolated Premature Thelarche and Thelarche Variant Isolated premature thelarche (IPT) is a benign condition characterized by early breast development in girls, usually under the age of 2 years, in the absence of any other pubertal changes. This is a self-limiting condition[102] and FH is unaffected.[103] A variant condition, termed thelarche variant, exhibits features intermediate between IPT and CPP.[104,105] There appears to be a continuum between IPT and CPP; approximately 15% of girls with IPT may progress to CPP.[106] The thelarche variant may be associated with the development of pubic hair and detectable oestradiol but FSH levels predominate. However, they do show increased GV and advanced skeletal maturation[105] but FH appears be unchanged.[107] Isolated Premature Menarche This condition is defined as cyclical vaginal bleeding in prepubertal girls without any other signs of puberty. Gonadotrophins are not raised but an endometrial echo is visible on ultrasound during the bleeding phase. However, as the differential diagnosis includes child sexual abuse and vaginal malignancy, examination under anaesthesia may be required if the history and examination are not typical. Although poorly understood, it appears to be a benign and self-limiting condition with unaffected FH.[108] Abnormalities of Adrenarche In some individuals adrenarche (adrenal puberty occurring between 6 years and 8 years) is associated with sufficient androgen production to cause pubic hair development which may be referred to as exaggerated adrenarche. When symptoms occur at an earlier age this is termed premature adrenarche. Commonly associated symptoms include a history of body odour, greasy skin and hair, weight gain and some mood disturbance. At presentation, children may be taller and have an advanced BA. Although prepubertal growth in affected girls is enhanced with respect to normal controls, this enhancement may be compensated for by a decrease in the pubertal growth component leading to a FH within the target range.[109,110] Central Precocious Puberty CPP has an incidence of 1 in 5000-10 000 children with a female to male ratio of greater than 20 : 1.[111] The spectrum of idiopathic CPP contains transient, alternating, slowly progressive and rapidly progressive forms.[112] Ninety-five per cent of girls with CPP have idiopathic CPP whereas over 50% of boys have an identifiable aetiology.[113] Acceleration of growth is almost invariable in CPP but these children will also show premature ossification and fusion of the growth cartilage and early cessation of growth. Girls who present before 6 years are reported to lose 12-15 cm in FH whereas those who present after 6 years lose 7-10 cm.[114] The risk of short stature is higher in children with associated GH insufficiency or limited potential to grow due to cranial or craniospinal irradiation. Early puberty may result in a greater sitting height to leg length ratio at FH as an indicator of the premature bone maturation. The interpretation of height gain from treatment in CPP patients should be judged cautiously as FH predictions are based on BA estimation, a technique based on reference data from normal healthy children. Gonadotrophin-independent Precocious Puberty GIPP is characterized by pubertal sex steroid levels with prepubertal or suppressed gonadotrophins. Excess secretion of the hormone leads to hypertrophy of the target tissue as well as acceleration of growth and bone maturation. The source of hormone production can be gonadal, adrenal (tumour or congenital adrenal hyperplasia, CAH), ectopic (gonadotrophin- or hCG-producing tumours) or exogenous. Additionally, the McCune-Albright syndrome produces discordant sexual development. This syndrome is characterized by irregular pigmented caf?-au-lait patches and polyostotic fibrous dysplasia. Pubertal signs are usually discordant with early bleeding in girls and no evidence of gonadotrophin cyclicity. In this condition, growth acceleration may also be due to hyperthyroidism or GH excess. It occurs due to a generalized mutation of part of the G protein in endocrine tissues leading to overactivity. In males, testoxicosis or familial male PP can lead to pubertal changes and growth acceleration. The testes are often small for the degree of virilization.[115] In all of these conditions the excess sex steroid production leads to advanced epiphyseal maturation which can predict the timing of the onset of central puberty as there is remarkable synchrony between the onset of central puberty and skeletal maturation across the various disorders of puberty.[116] Central puberty may occur due to exposure of the hypothalamus to high levels of sex steroids; this phenomenon is known as "priming". Although puberty tends to be delayed in hypothyroid children, severe longstanding hypothyroidism may cause GIPP probably mediated by TSH stimulation of the FSH receptor.[117] Characteristically, there is testicular enlargement without significant virilization in boys and breast development, uterine bleeding and multicystic ovaries in girls. Thyroxine treatment can lead to resumption of the normal consonance of puberty and catch-up growth.[118] However, FH may be reduced attributable to a rapid advance in epiphyseal maturation.[119] Delayed Sexual Maturation Primary Delay of Growth and Puberty This condition, often referred to as constitutional delay of growth and puberty (CDGP), typically affects boys. The clinical features include relative short stature for chronologic age, delayed puberty and delayed bone maturation in otherwise healthy adolescents. A relatively short upper body segment is common at presentation and persists at attainment of FH.[120] Although FH is predicted to be normal based on BA estimation, adolescents with CDGP are usually shorter than their mid-parental height.[120-123] There is often a family history of delayed puberty and a personal history of atopy.[124] The decrease in FH may be explained by the short stature at onset of puberty, shorter duration between onset of puberty and pubertal growth spurt and compromised peak GV.[125] A short course of testosterone enanthate or low doses of oxandrolone can accelerate the pubertal growth spurt without altering FH.[126,127] However, FH in boys with CDGP may be improved by treatment with aromatase inhibitors by delaying bone age progression.[128] Secondary Delay of Growth and Puberty A delay in puberty can be seen in virtually any chronic disease of childhood.[129] Several factors influence the degree to which growth and pubertal development are affected. These include age, duration of illness and its severity, nutritional status and medications. This form of delayed puberty is often mistaken for CDGP but may be more profound and protracted depending on the underlying condition. Hypogonadal Endocrinopathy Hypogonadism can be classified according to the serum gonadotrophin levels; high levels indicate primary gonadal failure and low levels indicate disorders at the hypothalamo-pituitary level. Hypogonadotrophic Hypogonadism In hypogonadotrophic hypogonadism, such as Kallman's syndrome, puberty may be completely absent. The pubertal component of the ICP model will be lacking so childhood growth will continue at its slowly declining rate. In untreated individuals growth will continue until the third decade and FH may actually be taller than average due to this persistence of the childhood component of growth. However, this results in abnormal body proportions with a relatively longer lower body segment. Short stature may be seen initially relative to chronologic age but a normal FH is achieved after sex steroid replacement.[130] Hypergonadotrophic Hypogonadism This condition results from a primary defect of the gonads which renders them unresponsive to gonadotrophins. A similar growth pattern to those affected by hypogonadotrophic hypogonadism is observed. However, the commonest cause of primary hypogonadism in boys is Klinefelter syndrome (47,XXY) which is associated with tall stature. Often there is a normal onset of puberty but pubertal arrest can occur at any stage. If spontaneous puberty does occur then the magnitude and timing of pubertal growth is reported to be normal, with a mean FH of 186 cm. The tall stature may be attributable to the extra sex chromosome. Although testes are of normal size and consistency at birth, they fail to grow normally during puberty and seldom exceed 4 mls. Testicular involution followed by androgen deficiency then frequently occurs. Salivary testosterone levels are significantly lower by 16 years of age.[131] In boys with prenatal testicular atrophy (e.g. "the vanishing testes") the childhood component of growth is reported to be normal. In girls with Turner syndrome, the commonest form of ovarian dysgenesis, the growth pattern is influenced by the skeletal problems (haploinsufficiency of SHOX) and the absence of oestrogens during adolescence. They usually demonstrate mild growth retardation in utero followed by slow growth during infancy with a delayed onset of the childhood component of growth and then slow growth during childhood. If the ovaries completely lack follicles the previous deterioration of growth rate will be further attenuated in puberty, due to absence of a growth spurt. Hypogonadism with Other Endocrinopathy Delayed puberty is often seen in patients with GH deficiency or a GH receptor defect. A common feature to both these conditions is low or lack of IGF-I function. This highlights the possible role of IGF-I in the regulation of puberty.[132,133] In type 1 diabetes mellitus (T1DM), pubertal delay has also been described. However, this was not confirmed in more recent studies where FH was unaffected. Nonetheless, the pubertal growth spurt in T1DM may be attenuated.[134] Primary hypothyroidism can also be associated with hypogonadotrophic hypogonadism which is reversible with thyroxine treatment.[135] Men with primary hypothyroidism have a subnormal LH response to GnRH but normal response to hCG. Their low free testosterone levels normalize after thyroxine treatment due to changes in SHBG concentrations.[135] Although children with primary hypothyroidism may continue to grow for a longer period after therapy is initiated, FH can still be restricted.[136] Cushing's disease is associated with a delayed onset or mid-pubertal arrest of puberty which is reversible after removal of the source.[137,138] GH deficiency is common following treatment of childhood onset Cushing's disease and may persist for many years.[139] Early investigation for diagnosis and treatment of GH deficiency is thus advocated.[140] FH within target range can be achieved but excess adiposity remains a potential long-term complication.[140] Disorders of Gonadal and Sexual Development Some conditions have already been discussed under the "hypergonadotrophic hypogonadism" section. Boys with mixed gonadal dysgenesis (45,X/46,XY) demonstrate short stature during childhood. This relates to the 45,X cell line and not the androgen deficiency. The severity of the short stature depends on the degree of mosaicism in a similar fashion to girls with Turner syndrome. Other abnormalities of the sex chromosomes in girls include 46,XY pure gonadal dysgenesis, 47,XXX and androgen insensitivity syndrome. Besides being influenced by abnormal sex hormone production or sensitivity in puberty; their growth may also be influenced by other growth-enhancing genes (of unknown nature) of the X- and Y-chromosomes. The Y-chromosomes as well as the supernumerary X-chromosomes in males may be associated with tall stature. Boys with 47,XYY are of normal size at birth but show an increase in GV from 2 years of age. At the time of pubertal onset the average 47,XYY boy is 7.6 cm taller than controls. The pubertal growth spurt is also larger and of longer duration resulting in a FH of 188 cm.[131] Girls with extra X-chromosomes do not generally have tall stature.[141,142] Girls who are 47,XXX have a reduced size at birth but demonstrate an increase in GV during mid childhood, akin to 47,XXY boys, owing to greater leg length. Pubertal growth spurt is reported to be of normal magnitude but occurs 6 months later than that of controls and their FH is normal. 46,XY girls with CAIS achieve a FH in between that of normal men and women.[89,143,144] Individuals with CAIS and intact gonads have a normal female pubertal growth spurt despite the lack of androgen action.[89] The FH of published cases of XX gonadal dysgenesis (XXGD) and XY gonadal dysgenesis (XYGD) were compared by Ogata et al.[145] The mean FH of XYGD patients was significantly greater than that of XXGD patients.[145] This lends support to the existence of Y-specific growth genes that promote statural growth independently of the effects of sex steroids.[146] The childhood component of growth is unaffected by early gonadectomy emphasizing the relative lack of importance of sex steroids in the prepubertal phase of normal growth.[147] In summary, there is ample evidence to suggest that sex steroids, particularly, oestrogen play a vital role in modulating linear growth through the systemic GH-IGF-I axis, as well as, at the level of the growth plate. 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