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By: William A. Weiss, MD, PhD

  • Professor, Neurology UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA

Endocrine consequences of weight loss in obese buy demadex 10 mg with mastercard, hyperandrogenic generic 10mg demadex visa, anovulatory women cheap 10 mg demadex otc. Do obese but metabolically normal women differ in intra-abdominal fat and physical activity levels from those with the expected metabolic abnormalities? Suboptimal second-trimester ultrasonographic visualization of the fetal heart in obese women: should we repeat the examination? Does advanced ultrasound equipment improve the adequacy of ultrasound visualization of fetal cardiac structures in the obese gravid woman? Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone 20mg demadex for sale. Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Complications and outcome of assisted reproduction technologies in overweight and obese women. Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals. The seventh report on the confidential enquiries into maternal deaths in the United Kingdom. Visceral fat mass is a good marker of insulin resistance and metabolic disturbance in women with polycystic ovary syndrome. The effect of increasing obesity on the response to and outcome of assisted reproductive technology: a national study. Effect of overweight and obesity on assisted reproductive technology-a systematic review. Abdominal visceral adiposity in the first trimester predicts glucose intolerance in later pregnancy. Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis. National Heart, Lung and Blood Institute/National Institutes of Diabetes and Digestive and Kidney diseases. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults-The Evidence Report. Greater beneficial effects of visceral fat reduction compared with subcutaneous fat reduction on parameters of the metabolic syndrome: a study of weight reduction programmes in subjects with visceral and subcutaneous obesity. Recommen- dations for weight gain during pregnancy in the context of the obesity epidemic. Greater maternal weight and the ongoing risk of neural tube defects after folic acid flour fortification. Rittenberg V, Sobaleva S, Ahmad A, Oteng-Ntim E, Bolton V, Khalaf Y, Braude P, El-Toukhy T. Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. Imaging techniques for measuring adipose-tissue distribution-a comparison between computed tomography and 1. Severe maternal hyperglycemia exacerbates the development of insulin resistance and Fatty liver in the offspring on high fat diet. Validity and reproducibility of ultrasonography for the measurement of intra-abdominal adipose tissue. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Obesity, obstetric complications and cesarean delivery rate ‒ a population- based screening study. Long-term effects of gestational diabetes on offspring health are more pronounced in skeletal growth than body composition and glucose tolerance. We studied the consequences of overweight and obesity with respect to fecundity, costs of fertility treatment and pregnancy outcome in subfertile women. Methods: We searched the literature for systematic reviews and large studies reporting on the effect of weight on both fecundity and pregnancy outcome in subfertile women. We collected data on costs of treatment with ovulation induction, intra-uterine insemination and in vitro fertilisation, as well as costs of pregnancy complications. We calculated, for ovulatory and anovulatory women separately, the number of expected pregnancies, complications and costs in a hypothetical cohort of 1000 normal weight, overweight and obese women each. Results: In our hypothetical cohort of 1000 women, compared to women with normal weight live birth was decreased by 14 and 15% (from 806 live births to 692 and 687 live births) in overweight and obese anovulatory women respectively, for ovulatory women it was decreased by 22 and 24% (from 698 live births to 546 and 531 live births), respectively. These outcomes were associated with an increase in the number of complications and associated costs leading to cost per live birth in anovulatory overweight and obese women were 54 and 100% higher than their normal-weight counterparts, for ovulatory women they were 44 and 70% higher, respectively.

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There are many causes of abnormal radioactive uptake order demadex 10mg line, including metastases buy demadex 10 mg otc, infection generic 10mg demadex otc, inflammatory arthropathies demadex 10mg cheap, fracture or other significant bone trauma. Bone scans have been used for the diagnosis of early osteonecrosis, which is often not apparent on x-ray. Recommendation: Bone Scanning for Select Use in Acute, Subacute, or Chronic Knee Pain Bone scanning is recommended for select use in patients with acute, subacute, or chronic knee pain to assist in diagnosing osteonecrosis, neoplasms, or other conditions with increased polyostotic bone metabolism, particularly if more than one joint is to be evaluated. Indications – Knee pain with suspicion of osteonecrosis, Paget’s disease, neoplasm, or other increased polyostotic bone metabolism. Strength of Evidence  Not Recommended, Insufficient Evidence (I) Rationale for Recommendations Bone scanning may be a helpful diagnostic test to evaluate suspected metastases, primary bone tumors, infected bone (osteomyelitis), inflammatory arthropathies, and trauma . There is no indication for bone scanning in cases where the diagnosis is felt to be secure, as bone scanning does not alter management. Bone scanning is minimally invasive, has minimal potential for adverse effects (essentially equivalent to a blood test), but is costly. Evidence for the Use of Bone Scans There are no quality studies evaluating the use of bone scans for the evaluation of knee pain. Indications – Knee pain from osteonecrosis with suspicion of subchondral fracture(s), or increased polyostotic bone metabolism. However, ordering a large, diverse array of inflammatory markers without targeting specific disorders for which there is clinical suspicion is not recommended. Indications – Knee pain with suspicion of inflammatory disorder, including infection. Strength of Evidence – Recommended, Insufficient Evidence (I) Rationale for Recommendation Erythrocyte sedimentation rate is the most commonly used systemic marker for non-specific inflammation. C-reactive protein is a marker of systemic inflammation that has been reported to be associated with an increased risk of coronary artery disease. Other non- specific markers of inflammation include an elevated ferritin and protein-albumin gap. They are recommended as a reasonable component of the evaluation when there is suspicion of a systemic inflammatory condition. Evidence for the Use of C-Reactive Protein, Erythrocyte Sedimentation Rate, and Other Non- specific Inflammatory Markers There are no quality studies evaluating the use of C-reactive protein, erythrocyte sedimentation rate, and other non-specific inflammatory markers for knee pain. These injections are also sometimes used to differentiate pain from a distant site, such as the hip or spine. Diagnostic injections include intraarticular injections (knee, hip, or sacroiliac), ilioinguinal, genitofemoral, and saphenous nerve blocks, and lumbar epidurals. Indications – Subacute or chronic knee pain from an unclear source; immediate and delayed results of injection(s) should be recorded. Strength of Evidence  Recommended, Insufficient Evidence (I) Rationale for Recommendation Local anesthetic injections may be helpful for confirming diagnostic impressions, although there are no quality studies evaluating the use of injections for these purposes. Intraarticular knee injections are often performed with anesthetic agents and glucocorticosteroids, as this generally accomplishes both diagnostic and therapeutic purposes simultaneously. These injections are minimally invasive, have minimal potential for adverse effects, and are moderately costly. Evidence for the Use of Local Anesthetic Diagnostic Injections There are no quality studies evaluating the use of local anesthetic diagnostic injections for knee pain. Electrodiagnostic studies have also been used to confirm diagnostic impressions of other peripheral nerve entrapments, including of the lateral cutaneous nerve of the thigh (meralgia paresthetica). Indications – Subacute or chronic paresthesias with or without pain, particularly with an unclear diagnosis. Strength of Evidence  Recommended, Insufficient Evidence (I) Rationale for Recommendation Electrodiagnostic studies may assist in confirming peripheral nerve entrapments. These studies are minimally invasive, have minimal potential for adverse effects (essentially equivalent to a blood test), and are moderately costly. Evidence for the Use of Electromyography There are no quality studies evaluating the use of electrodiagnostic studies for diagnosing peripheral nerve entrapments relevant to the knee. Indications – Subacute or chronic knee pain in which imaging of surrounding or intraarticular soft tissues is needed (including menisci); evaluation of moderately severe and severe cruciate ligament sprains and tears to evaluate the extent of the injury and help determine whether surgery is indicated. These studies are also likely to be helpful for those with certain post-operative indications, including after chondrocyte implantation. However, it is likely the best imaging procedure available for certain select patients. It should be noted that the threshold for x-ray of the lumbosacral spine and/or hip joint should be low, particularly if the findings on knee x-ray are either normal or do not readily explain the degree of clinical findings. Early x-rays are usually normal or have less distinct trabecular patterns, but as the disease progresses, x-rays begin to show osteoporotic areas progressing to sclerotic areas and flattening and bony collapse. Recommendation: X-ray for Evaluating Acute, Subacute, or Chronic Knee Pain X-ray is recommended for evaluating acute, subacute, or chronic knee pain. Indications – In the absence of red flags, knee pain of moderate to severe intensity lasting at least a few weeks, and/or limited range of motion. For patients with chronic or progressive knee pain, it may be reasonable to obtain a second set of x-rays, months to years after the baseline x-rays to re-evaluate the patient’s condition, particularly if symptoms change. Recommendation: X-ray for Diagnosing Fracture X-ray is recommended for diagnosing fracture. Indications – Patients thought to have fracture, particularly those with an inability to bear weight, effusion, or ecchymosis. Strength of Evidence – Recommended, Insufficient Evidence (I) Rationale for Recommendations X-ray is helpful in evaluating most knee pain, both to diagnose and to assist with narrowing the differential diagnosis.

And if the patient is in the high-cure category buy demadex 20mg on-line, does it make any difference what the receptor status is? Patients and clinicians have to incorporate all of the above considerations into this medical decision order demadex 20mg on line. But when all is said and done order 10mg demadex overnight delivery, patients have to take an unknown risk if they want the benefits of hormone treatment generic demadex 10 mg without prescription, and clinicians have to take an unknown medical-legal risk. Some patients will choose to take hormones, judging the benefits to be worth the unknown risk. Until data are available from appropriate clinical trials, there is no right or wrong decision. Women With Cardiovascular Disease Is the woman with a previous history of a cardiovascular event, such as a myocardial infarction or stroke, the very woman who needs the protection of estrogen against cardiovascular disease? In the Leisure World study, estrogen users with previous myocardial infarctions, 43 strokes, or hypertension had a 50% reduction in risk for death from a subsequent stroke or myocardial infarction. In the Lipids Research Clinics study, the cardiovascular mortality in women with previous cardiovascular disease was reduced 85%. And most impressively, in women with severe coronary disease 395 (documented by arteriography), estrogen users had a 97% survival rate at 5 years compared with a significantly different 81% rate in nonusers. In women with mild to moderate disease, there was no difference at 5 years, but at 10 years, estrogen users had a 96% survival rate compared with 85% in nonusers. In women who have 397 undergone coronary artery bypass surgery, the 10-year survival rate in estrogen users was 81. In women who have been treated with estrogen after coronary angioplasty, case-control analysis indicated that the treated women had a better survival rate and experienced fewer subsequent 398 myocardial infarctions. The number of patients on estrogen-progestin was too small in this study for analysis. A retrospective cohort study in Seattle determined prognosis in women surviving a myocardial infarction and detected a 36% reduced risk of re-infarction in current estrogen users, although small numbers prevented 399 the achievement of statistical significance. These studies all indicate reduced risks for adverse clinical events and support the use of postmenopausal hormone therapy in women with coronary heart disease. Imaging studies have documented a reduction in intimal thickening in postmenopausal women who are estrogen users compared with nonusers, and this beneficial 400, 401 effect is not compromised by the addition of a progestational agent to the treatment regimen. Thus, postmenopausal hormonal therapy can bring about a 400, 402 reduction in atherosclerosis, and this effect is comparable with that produced by a lipid-lowering drug. Decision making will be easier as the results of more clinical trials become available. Until then, in our opinion, estrogen treatment with the appropriate, standard dose is indicated and safe for patients with cardiovascular disease. We should emphasize, however, that excellent preventive results are obtained with the usual armamentarium of drugs employed by cardiologists for the treatment of coronary heart disease. The hormonal effects were even greater in women who had abnormal lipids or atherosclerosis. Thus, both treatments produce beneficial effects, and it is not known whether the differences are clinically important. The dose of estrogen is very important because it is becoming increasingly apparent that the beneficial cardiovascular effects of estrogen are restricted to a relatively narrow therapeutic window; the benefits may be reduced at doses of estrogen greater than that equivalent to 0. Women With Diabetes Mellitus A strong argument can be made that postmenopausal women with diabetes mellitus can benefit from the cardioprotective actions of estrogen. Indeed, in prospective studies of postmenopausal women with noninsulin-dependent diabetes mellitus, 404, 405 estrogen treatment improved all glucose metabolic parameters, including insulin resistance, the lipoprotein profile, and measurements of androgenicity. These changes should reduce the risk of cardiovascular disease; however, long-term studies are yet to be available. Tibolone also has a beneficial impact in short-term 208, 209 studies on insulin resistance in normal women and in women with noninsulin-dependent diabetes mellitus. Women With Liver Disease Osteoporosis is a major consequence of chronic liver disease. Although other bone-preserving agents can be utilized, none provides the multisystem benefits associated with estrogen therapy. In an evaluation of liver chemistries in a group of patients with primary biliary cirrhosis, standard hormone therapy doses produced 406 no adverse changes over a period of one year. We recommend measurement of liver chemistries after one month of treatment, and every 6 months, with continuing hormone therapy in the absence of deterioration. The Vaginal Administration of Estrogen Many clinicians believe that estrogen administered intravaginally is not absorbed, and systemic effects can be avoided. However, estrogen is absorbed very readily 407 from a vagina with immature, atrophic mucosa. Indeed the initial absorption is rapid, and relatively high circulating levels of estrogen are easily reached. This decline takes approximately 3–4 months, after which lesser, but still significant absorption takes place. European studies have demonstrated that vaginal maturation can be achieved with a vaginal ring (which is left in place for 3 months) having incredibly small doses of 409, 410 estrogen, with a low-level of systemic absorption. This is an acceptable method to relieve atrophic vaginal symptoms in women with contraindications to estrogen treatment. Other Conditions Close surveillance is indicated for some patients with seizure disorders, familial hyperlipidemias (elevated triglycerides), and migraine headaches. Patients with migraine headaches often improve if a daily, continuous method of treatment is used, eliminating a cyclic change in hormone levels that can serve to trigger headaches. Conditions that do not represent contraindications include controlled hypertension, diabetes mellitus, smoking, and varicose veins.

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With increasing estrogen levels in late gestation purchase 10 mg demadex with visa, even greater 11b-hydroxysteroid dehydrogenase activity would result in even less maternal cortisol reaching the fetal circulation demadex 20mg cheap. A relative deficiency in 11b-hydroxysteroid dehydrogenase type 1 46 discount 10 mg demadex mastercard, 47 (the placental isoform) is correlated with low birth weight discount demadex 20mg on-line, which in turn is correlated with insulin resistance, abnormal lipids, and hypertension in adult life. This 48 enzyme is abundantly expressed in syncytiotrophoblast at the interface between fetal tissue and maternal blood. Expression of the second isoform, type 2 11b-hydroxysteroid dehydrogenase, is found in the liver and the distal nephron of the kidney where enzyme activity excludes glucocorticoids from mineralocorticoid 49 receptors. Fetal hypoxemia down-regulates fetal renal expression of the type 2 enzyme, potentially affecting glucocorticoid availability. In the fetal adrenal, the beta-subunit is not expressed; thus, inhibin A and activin A are the principal forms. Inhibin consists of two dissimilar peptides, alpha- and beta-subunits, linked by disulfide bonds. Inhibin A and inhibin B each contain an identical alpha-subunit, but distinct beta-subunits. Activin contains two subunits that are identical to the beta-subunits of the inhibins. Perhaps activin plays this role in the remodeling of the fetal zone in the newborn. Evidence indicates that the epidermal growth factor receptor is activated in the fetal adrenal, but the ligand using this receptor is probably transforming growth factor-a. Like activin, transforming growth factor-b inhibits fetal zone cellular proliferation, and in addition, suppresses steroidogenesis. The unique features of the fetal adrenal gland can be ascribed to its high-estrogen environment. Tissue culture studies have demonstrated that hormonal peptides of 60, 61and 62 pituitary or placental origin are not the factors that are responsible for the behavior of the fetal adrenal gland. Estradiol concentrations of 10–100 ng/mL are required to inhibit cortisol secretion. A study of the kinetics of 3b-hydroxysteroid dehydrogenase activity in human adrenal microsomes reveals that all steroids are inhibitory, and 65 most notably, estrone and estradiol at levels found in fetal life cause almost total inhibition. In a study utilizing a human adrenocortical cell line, estradiol in high 66 concentrations inhibited 3b-hydroxysteroid dehydrogenase and the mechanism appeared to be independent of the estrogen receptor. It continues to be uncertain, however, whether the internal microenvironment of the adrenal gland can be affected by the exogenous administration of steroids. In the monkey, epidermal growth factor can increase the 3b-hydroxysteroid dehydrogenase content in the fetal adrenal gland, but it is not 69 clear how this action is regulated. With birth and loss of exposure to estrogen, the fetal adrenal gland quickly changes to the adult type of gland. Measurement of Estrogen in Pregnancy Because pregnancy is characterized by a great increase in maternal estrogen levels, and estrogen production is dependent on fetal and placental steroidogenic cooperation, the amount of estrogen present in the maternal blood or urine reflects both fetal and placental enzymatic capability and, hence, well-being. Attention focused on estriol because 90% of maternal estriol is derived from fetal precursors. The end product to be assayed in the maternal blood or urine is influenced by a multitude of factors. Availability of precursor from the fetal adrenal gland is a prime requisite as well as the ability of the placenta to perform its conversion steps. Maternal metabolism of the product as well as the efficiency of maternal renal excretion of the product can modify the daily amount of estrogen in the urine. Blood flow 70, 71 to any of the key organs in the fetus, placenta, and mother becomes important. The response to acute stress is in contrast to the effect of chronic uteroplacental insufficiency which is associated with a reduction in fetal androgens and maternal estrogens. In addition, drugs or diseases can affect any level in the cascade of events leading up to the assay of estrogen. For years, measurement of estrogen in a 24-hour urine collection was the standard hormonal method of assessing fetal well-being. Because of its short half-life (5–10 minutes) in the maternal circulation, unconjugated estriol has less variation than urinary or total blood estriol. However, assessment of maternal estriol levels has been superseded by various biophysical fetal monitoring techniques such as nonstress testing, stress testing, and measurement of fetal breathing and activity. Modern screening for fetal aneuploidy (discussed later in the chapter) utilizes 3 markers in the maternal circulation: alpha fetoprotein, human chorionic gonadotropin, and unconjugated estriol. Amniotic Fluid Estrogen Measurements Amniotic fluid estriol is correlated with the fetal estrogen pattern rather than the maternal. Most of the estriol in the amniotic fluid is present as 16-glucosiduronate or as 3-sulfate-16-glucosiduronate. Very little unconjugated estriol is present in the amniotic fluid because free estriol is rapidly transferred across the placenta and membranes. Estriol sulfate is low in concentration because the placenta and fetal membranes hydrolyze the sulfated conjugates, and the free estriol is then passed out of the fluid. Because the membranes and the placenta have no glucuronidase activity, the glucosiduronate conjugates are removed slowly from the fetus. The glucosiduronates therefore predominate in the fetal urine and the amniotic fluid.

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Because of the irreversible nature of the inhibition by aspirin generic demadex 10 mg free shipping, aspirin exerts a long lasting effect on platelets discount demadex 10mg line, maintaining inhibition in the platelet for its lifespan (8–10 days) buy 20 mg demadex mastercard. Prostacyclin synthesis in the endothelium recovers more quickly because the endothelial cells can resynthesize new cyclooxygenase 20 mg demadex visa. The sensitivity of the platelets to aspirin may explain the puzzling results in the early studies in which aspirin was given to prevent subsequent morbidity and mortality following thrombotic events. It takes only a little aspirin to effectively inhibit thromboxane synthesis in platelets. Going beyond this dose will not only inhibit thromboxane synthesis in platelets, but also the protective prostacyclin production in blood vessel walls. Others indicate that the dose which effectively and selectively inhibits platelet cyclooxygenase is 20–40 mg daily. The Endocrinology of Parturition Perhaps the best example of the interplay among fetus, placenta, and mother is the initiation and maintenance of parturition. Hormonal changes in the uteroplacental environment are the principal governing factors accounting for the eventual development of uterine contractions. The sequence of events has been repeatedly 247, 248 and 249 reviewed in detail, where references to the original work are available. Extensive work in the sheep has implicated the fetal pituitary-adrenal axis in normal parturition. Increased cortisol secretion by the fetal adrenal gland starts a chain of events associated with labor. This change is brought about by the induction of 17a-hydroxylase, 17,20-lyase enzyme activity (P450c17) in the sheep placenta. Glucocorticoid treatment of sheep placental tissue specifically increases the rate of production of 17a,20a-dihydroxypregn-4-en-3-one. This dihydroxyprogesterone compound also has been identified in sheep placental tissue obtained after spontaneous labor. Thus, direct synthesis of progesterone does not decline, but increased metabolism to a 17a-hydroxylated product results in less available progesterone. Progesterone withdrawal is associated with a decrease in the resting potential of myometrium; i. Conduction of action potential through the muscle is increased, and the myometrial excitability is increased. Dihydroxyprogesterone also serves as a precursor for the rise in estrogen levels, which occurs a few days prior to parturition. Estrogens enhance rhythmic contractions, as well as increasing vascularity and permeability, and the oxytocin response. Thus, progesterone withdrawal and estrogen increase lead to an enhancement of conduction and excitation. Human Parturition the steroid events in human pregnancy are not identical to events in the ewe. Steroid changes in the sheep occur over the course of several days, while in human pregnancy the changes begin at approximately 34–36 weeks and occur over the last 5 weeks of pregnancy. However, if the time course is expressed as a percentage of gestational length, the percentages in sheep and primates are impressively comparable. Cortisol rises dramatically in amniotic fluid, beginning at 34–36 weeks, and correlates with pulmonary maturation. Cord blood cortisol concentrations are high in infants born vaginally or by cesarean section following spontaneous onset of labor. In contrast, cord blood cortisol levels are lower in infants born without spontaneous labor, whether delivery is vaginal (induced labor) or by cesarean section (elective repeat section). In keeping with the extended time scale of events, administration of glucocorticoids is not followed acutely by the onset of labor in pregnant women (unless the pregnancy is past due). It is unlikely that the cortisol increments in the fetus represent changes due to increased adrenal activity in the mother in response to stress. Although maternal cortisol crosses the placenta readily, it is largely (85%) metabolized to cortisone in the process. This, in fact, may be the mechanism by which suppression of the fetal adrenal gland by maternal steroids is avoided. In contrast to the maternal liver, the fetal liver has a limited capacity for transforming the biologically inactive cortisone to the active cortisol. On the other hand, the fetal lung does possess the capability of changing cortisone to cortisol, and this may be an important source of cortisol for the lung. Increased fetal adrenal activity is followed by changes in steroid levels as well as important developmental accomplishments . In human parturition an important contribution of the fetal adrenal, in addition to cortisol, is its effect on placental estrogen production. The common theme in human pregnancies associated with failure 250 to begin labor on time is decreased estrogen production; e. In contrast, mothers bearing fetuses who cannot 251 form normal amounts of cortisol, such as those with congenital adrenal hyperplasia, deliver on time. Progesterone maintenance of uterine quiescence and increased myometrial excitability associated with progesterone withdrawal are firmly established as mechanisms of parturition in lower species. In primates, the role of progesterone is less clear, largely because of the inability to demonstrate a definite decline in 252 peripheral blood levels of progesterone prior to parturition. Nevertheless, pharmacologic treatment with progesterone or synthetic progestational agents has some 253, 254 effect in preventing premature labor, although not labor at term. There is also reason to believe that progesterone concentration is regulated locally, especially 255 in the fetal membranes and the decidua, and progesterone withdrawal can be accomplished by a combination of binding and metabolism. Furthermore, inhibition of progesterone production in the second trimester of human or the third trimester of monkey pregnancies is followed by a decrease in maternal, fetal and amniotic fluid progesterone concentrations and preterm labor and 257, 258 delivery. Perhaps multiple mechanisms exist, which affect in a subtle fashion the local concentration and actions of progesterone, as well as the production of 259 progesterone in fetal membranes.

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