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Therapies that target key cellular pathways/attributes specific for Because the cognate antigen for a particular BCR is usually not tumor cells are envisioned as a better way to treat cancer trusted 20mg levitra impotence low testosterone. In certain known generic 20 mg levitra free shipping erectile dysfunction medication names, this binding is often experimentally modeled with an diseases, such as chronic myelogenous leukemia, targeted therapies antibody reagent derived from immunoglobulin generated in a have substantiated this vision. It has long been suspected that the nonhuman species and directed against constant regions of human B-cell receptor (BCR), the defining attribute of normal and neoplas- IgH or IgL. BCR “cross-linking” with this reagent mimics the tic B cells, would be an effective target in BCR-expressing malignan- binding of polyvalent antigen and initiates a rapid cascade of cies. Recent years have seen a convergence of new preclinical evidence well-known proximal phosphorylation events, involving multiple that BCR signaling is critical to most B-cell malignancies, the kinases and adaptor molecules including Src family kinases (SFK, development of clinic-ready targeted agents inhibiting BCR-activated chiefly LYN), spleen tyrosine kinase (SYK), Bruton tyrosine kinase signaling pathways, and clinical trials demonstrating the striking (BTK), and PI3K. Active BCR signaling is therefore “druggable” effectiveness of these agents. Despite the success of BCR-targeting 1 by small-molecule inhibitors (SMIs) of several kinases, potentially therapy for B-cell malignancies, summarized in a recent review article, preventing the activation of one or more of the distal signaling questions remain about how best to translate BCR-targeting therapy to pathways that drive proliferation, growth, and survival: NF- B, the clinical setting. This review discusses briefly the molecular biology NFAT, MAPK, and AKT/mTOR. Most evidence Molecular biology of BCR signaling in B-cell supporting this implication comes from chronic lymphocytic leuke- malignancies mia/small lymphocytic lymphoma (CLL/SLL), which can be di- A B cell is defined and created by the productive rearrangement of vided into 2 types of cases. In unmutated (U) cases, the variable (V), immunoglobulin heavy (IgH) and light (IgL) chain genes, leading to diversity (D), and joining (J) segments of the IgH and IgL genes that Hematology 2013 553 have been selected by recombination to encode HVRs have ABC-DLBCL cell lines. Sequencing found that most of these lines, germline sequences. In mutated (M) cases, these segments have and 24% of primary ABC-DLBCL tumors, had mutations in the undergone somatic hypermutation, the normal process in germinal immunoreceptor tyrosine activation motif (ITAM) domains of centers by which the affinity of BCR for its cognate antigen is CD79A and CD79B genes, which normally serve as substrates for increased. Both U and M cases display “stereotyped” nonrandom phosphorylation by SFK and activation of SYK via its tandem SH2 utilization of V, D, and J segments, and HVRs from some M cases domains. The molecular consequences of these ITAM mutations is have identical nucleotide sequences, both of which imply selection not entirely clear, although they appear to enhance BCR signaling for binding to a common self-antigen. Although the BCR of CLL by promoting surface BCR expression and reducing signal- cells has often been considered to resemble “natural” polyreactive terminating LYN kinase activity. Nonetheless, the frequency of antibodies characteristic of normal marginal zone B cells, specific these BCR-activating mutations in primary tumors is strong evi- antigens recognized by CLL/SLL cells have been identified, mostly dence for “chronic active” BCR signaling in ABC-DLBCL. Of of self-origin2,3 but also of fungal origin in some cases. After productive have nonstereotyped BCRs that bind to a common autoantigen in IgH rearrangement, early B-cell precursors in the BM express a the N-terminal region of vimentin. In the periphery, mature B cells continue to depend on tonic by the HVR: unusually frequent mutations in IgH scaffold regions BCR signaling, as shown by their disappearance upon conditional lead to abnormal sites of N-glycosylation in FL IgH chains,9 which 19 deletion of IgH or CD79A. In contrast, conditional deletion of may be bound by microenvironmental lectins and trigger BCR members of the CARD11/ BCL10/MALT1 complex, essential for signaling. Frequent (70%) mutations in TCF3 or its malignancies has additional implications. One is that self-reactivity negative regulator ID3 in BL cell lines and primary tumors were by B-cell malignancies implies a defect in tolerance mechanisms found to be associated with increased expression of IgH and IgL, that normally prevent development of self-reactive B cells. Al- and RNA interference studies showed dependence on CD79A and SYK but not CARD11. This was found to be the case for the activated B-cell (ABC) tions. In acute and chronic active BCR signaling, BTK is subtype of diffuse large B-cell lymphoma (DLBCL), originally phosphorylated by SYK and then phosphorylates phospholipase defined by having a gene expression profile with similarities to that C 2, leading to activation of protein kinase C beta and, in turn, of normal memory B cells activated by acute BCR cross-linking,14 CARD11. Ibrutinib (PCI-32765) is an orally available, selective and subsequently found to depend on NF- B activation by the kinase inhibitor that irreversibly binds to the Cys-481 residue of CARD11/ BCL10/MALT1 complex. Early preclinical studies demonstrated ibrutinib’s ability to found that the viability of most ABC-DLBCL cell lines was block BCR signaling in normal peripheral B cells and induce compromised by knock-down of several signaling proteins down- response in animals with lymphoma. No cumulative hematologic with 2 IgH and 2 IgL disulfide bond-linked chains to comprise the or nonhematologic toxicity was reported in patients with pro- BCR, were also found to be required for viability of BCR-dependent longed dosing. There was no significant reduction in normal 554 American Society of Hematology Figure 1.

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Withdrawals due to adverse events were reported in 5 trials cheap levitra 20 mg with amex erectile dysfunction drug companies. Three favored short-acting 33 cheap 20 mg levitra overnight delivery erectile dysfunction foods, 38, 39 34 36 opioids, 1 favored long-acting, and 1 was equivocal. These data were limited by the poor quality of the trials for adverse event assessment and the fact that 2 of the trials evaluated the same (rerandomized) population. Long-acting opioid analgesics 33 of 74 Final Update 6 Report Drug Effectiveness Review Project Table 7. Adverse events in trials of long-acting compared with short-acting opioids Study Year (Quality rating) Opioid Nausea Vomiting Constipation Drowsiness Dizziness Confusion Withdrawals Long-acting 15% 6% 71% 53% 12% 9% NR 34 oxycodone (5/34) (2/34) (24/34) (18/34) (4/34) (3/34) Caldwell 1999 (POOR) Short-acting 38% 11% 54% 70% 24% 14% oxycodone + NR (14/37) (4/37) (20/37) (26/37) (9/37) (5/37) acetaminophen Long-acting 15% 2% 38% 11% 13% 4% 36 NR Hale 1999 oxycodone (7/47) (1/47) (18/47) (5/47) (6/47) (2/47) (POOR) Immediate-release 26% 0% 36% 11% 9% 2% NR oxycodone (12/47) (0/47) (17/47) (5/47) (4/47) (1/47) Long-acting 50% 20% 30% 27% 30% 3% 20% Salzman oxycodone (15/30) (6/30) (9/30) (8/30) (9/30) (1/30) (6/30) 39 1999 (POOR) Short-acting 33% 4% 37% 37% 22% 0% 7% oxycodone (9/27) (1/27) (10/27) (10/27) (6/27) (0/27) (2/27) 31% 10% 19% 10% 17% 25% 33 Long-acting codeine NR Hale 1997 (16/52) (5/52) (10/52) (5/52) (9/52) (13/52) (POOR) 18% 2% 16% 4% 4% 8% Short-acting codeine NR (9/51) (1/51) (8/51) (2/51) (2/51) (4/51) Long-acting 37. Long-acting opioid analgesics 34 of 74 Final Update 6 Report Drug Effectiveness Review Project Key Questions 5 and 6. Are there subpopulations of patients (specifically by race, age, sex, socio-economic status type of pain, or comorbidities) with chronic noncancer pain for which one long-acting opioid is more effective or associated with fewer harms, or for which long-acting opioids are more effective or associated with fewer harms than short-acting opioids? Summary of evidence • The evidence regarding differential efficacy or adverse event risk from long-acting opioids or between long-acting and short-acting opioids in subpopulations of patients with noncancer pain was severely limited in quantity and quality and it was not possible to draw reliable conclusions regarding comparative efficacy or adverse event rates for any subpopulation from these data. Detailed assessment No clinical trials or observational studies were designed to compare the efficacy of long-acting opioids for different races, age groups, or genders. Race was rarely reported in the trials and when it was reported the overwhelming majority of patients were white. Women were well- represented in the trials (slightly over 50%). The average age of included patients was in the 47 11, 34 mid-50s, though 1 study evaluated patients with an average age of 70 years. Two trials performed very limited subgroup analysis on older patients. Neither trial directly compared a long-acting opioid to another. They provided little information regarding differential efficacy or adverse events within the class of long-acting opioids. One fair-quality retrospective cohort study found that the risk of constipation associated with long-acting oxycodone compared with transdermal fentanyl was higher in patients older than 65 years (adjusted odds ratio, 7. Because there was a high likelihood for unmeasured or unknown confounders, firm conclusions from this subgroup analysis were not possible. A post-hoc analysis of 2 placebo-controlled trials examined the effects of age, sex, and 63 prior opioid use on response to extended-release oxymorphone in patients with low back pain. Both trials included a titration phase and a 12-week, randomized treatment phase. Only those patients who responded to oxymorphone treatment in the titration phase continued into the randomization phase (347 of 575; 60. There were no significant effects of age, sex, or prior opioid experience on the visual analogue scale-measured pain intensity and no effect of the measured factors on discontinuations due to lack of efficacy in the oxymorphone group. There were no significant differences in the occurrence of adverse effects based on age or sex. Constipation occurred more frequently in opioid-naïve patients during titration, but the difference was not significant during the treatment phase. Because it included only trials of 1 drug, this analysis did not provide evidence for comparative effectiveness or safety in subgroups. Long-acting opioid analgesics 35 of 74 Final Update 6 Report Drug Effectiveness Review Project Different types of chronic noncancer pain patients were studied in trials, including back pain, osteoarthritis, phantom limb pain, and neuropathic pain. Subgroups of trials for specific types of pain had the same problems with heterogeneity in interventions, outcomes assessed, and findings that were encountered in examining general efficacy and adverse events. They were further limited by the smaller number of available trials for each type of pain. These trials provided insufficient indirect evidence that a long-acting opioid is superior to any other in any subpopulation of patients with chronic pain. SUMMARY Strength of Evidence The results of this review are summarized in Table 8, below, and Appendix E summarizes the strength of the evidence for each key question.

Massive contraceptive support is abstinence buy levitra 10 mg free shipping erectile dysfunction pump cost, the fertility awareness-based method needed to reach the Millennium Development (FAB) is the only FP allowed since 1951 order 10mg levitra otc erectile dysfunction at age 25, by the Goals (MDGs) and International Conference on Roman Catholic Church (RCC) and then of Population and Development (ICPD) goals and course only within marriage. The method can work well for a longer existing, IUDs and implants constitute the LARC group middle class, stable partnership with already a few (some countries include DMPA), also called ‘fit and children, in which sex is discussable and negotiable, forget’ methods [see also UK National Institute for partners respect each other and one or two extra Health and Clinical Excellence (NICE) guidelines5]. Disharmony is more like- A woman can start on LARC at any time in her ly if he wants seven children and she three, or when menstrual cycle, provided that you can be reasonably they see each other only occasionally. If FAB is not certain she is not pregnant (Boxes 3 and 4). LARCs used for religious reasons, barrier methods can be need little client attention for years other than notic- used during possible fertile days. It takes about ing an IUD expulsion and it is good if she checks the 3 months of supervised observation of their own threads monthly with IUDs. Hence, there is little cycle to become proficient in the method, while difference between typical use and perfect use of RCC-controlled courses are often only offered to LARCs (Table 1). This difference is sometimes the married, making it difficult for couples to post- enormous for other non-permanent methods, espe- pone their first pregnancy. Moreover, there are cially if used by those not yet in a stable relationship 152 Contraception Box 4 When to start and when does protection start If according to Box 3 the client is unlikely to be nant. They are immediately effective, even pregnant then (modern) methods can be started any retrospectively, if used as EC (see under Emer- day but not all are effective at once. Consult not breastfeeding, a COC can be started from Box 3 and for extra considerations, the section day 21 post-partum (if there are no extra throm- on female sterilization. If she could be pregnant botic risk factors) and COCs are then effective but it is too early to tell and she has succeeded directly. If there are these extra risk factors [such in getting on the operation list only after a lot of as high body mass index (BMI), post-cesarean], trouble, perform the operation anyway: it does then – after post-partum day 42 – being post- not cause a miscarriage, there is maximum 25% partum is not a risk factor anymore and COC chance she became pregnant this cycle and if eligibility is decided as per Box 2. By this time she is pregnant she will at least be protected in when non-breastfeeding CSAOUCFAW future. There are no known side-effects to EC could be repeated or, better, a Cu IUD the pregnancy if COC or progestogen-based could be inserted. Continue previous reliable method (unless • PBC are effective directly if given in the first 5 partner is pregnant) or – less reliable – days of the cycle (LNG-IUD up to 7 days), or CSAOUCF 3 months. In all • After proper COC, CHC ring or CHC patch other cases except during lactation amenorrhea use, the stop week (real stop or use of placebo method (LAM): CSAOUCFAW. If on POP, give LARC/ nancy can’t be completely excluded and even if DMPA/COC or TO during POP use, stop CSAOUCFAW is unrealistic. Cu IUD and TO are effective not harm the pregnancy and a pregnancy test (or directly. Also on day of: miscarriage; first- to DMPA, LARC or TO. There are theoretical and second-trimester abortion; ectopic opera- concerns of possible virilization of a female fetus tion; removal of LNG-IUD; removal of with use of DMPA and implants, but they are previous implant; post-partum discharge. If, while waiting LARC on the day next injection was due with for the results, CSAOUCFAW is unrealistic, 14 days ‘grace period’ to have direct effect. This happened in the because of their age, unlikely to get pregnant. Make it known that the side-effects reversibility of LARCs, unlike TOs, makes LARC a can be a nuisance but are not dangerous and mostly good option for women who want to postpone hav- the advantages overshadow them. After removal ing children, who want to space, or who are not yet there is a quick return to fertility. All LARCs are The method can be used by nearly every woman suitable for women who have a high BMI, a history (Box 2) whether she has a completed family or of ectopic, of DVT or migraine with aura, HIV, are wants to space, or postpone her first pregnancy. This is WHO teaching, but studies Dedicated staff can make an enormous contribu- show that an implant inserted just before post-par- tion to reproductive health if there is access to tum discharge is also fine: a US study showed that LARCs6. LARCs are, if used their whole lifespan, placing an implant just before discharge from hospi- in general more cost-effective than COC, POP or tal after delivery does not affect breastfeeding7. This DMPA, certainly when the costs of unintended is a good idea if there are transport problems. Prices under different circum- and they make the cervical mucus impenetrable stances in different countries differ enormously for for sperms. They protect from PID but not from STI LARCs, up to a factor of 50 more in some instanc- urethritis/cervicitis/syphilis. All progestogen-based contracep- most economical, good for at least 10 years.

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Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events K atrak Tone: 0-5 scale (1=flaccid;5=severe) F A IR buy levitra 10mg cheap psychological reasons for erectile dysfunction causes. A ctivities ofdaily living: N o between-group specified) differences L eth argy/drowsiness: 14/20 vs buy generic levitra 10 mg online erectile dysfunction how can a woman help. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics K nutsson R andomiz ed A : Tiz anidine, N otreported 13 G ender: 4/17 (24% )female 101 crossovertrial maximum 10 mg/day A ge range: 23-80 1982 12 R ace: notreported Sweden B: Placebo Illness duration: 2 month s to 42 years Single center 3-4 weeks intervention,3-4 W h eelch air-bound: 3/17 (18% ) weeks crossover W alking-aid dependent: 8/17 (47% ) Priorantispasticmedicationuse Baclofen: 4/14 (29% ) Dantrolene sodium: 1/4 (25% ) K urtz ke R andomiz ed A : M etaxalone 400 Patients with 36 M etaxalone vs. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events K nutsson R esistance to passive movement:5-point F A IR. R andomiz ation, Tiz anidine vs placebo W ith drawals (due to adverse 115 A sh worth scale allocationconcealment, Passive resistance/A sh worth scale (improvement): events): 1 (patientonplacebo) 1982 C lonus: unspecified 3-pointscale eligibility criteria,blinding 5/12 (42% )vs. N otclearif M etaxalonenvs placebo W ith drawals (due to adverse 55 pounds allocationconcealment M eanch ange inresistance to passive movement events): 2/14 vs. Dry mouth : none reported Skeletal Muscle Relaxants Page 144 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 4. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics L apierre R andomiz ed A : Tiz anidine 2 A ge between18 66 Tiz anidine vs. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events L apierre N eurologicalevaluation: included scoringof F A IR. R andomiz ation, N eurologicalevaluation: no significantbetween- Tiz anidine vs. K urtz ke EDSS: N o between-groupdifferences events):cleardata notprovided C umulative limbtone score (ch ange from Tolerability: 53% vs. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics L osin R andomiz ed A : C h lorz oxaz one, C h ildrenwith 30 M eanage (years): 10 107 average dose of20 severe spasticity, F emale gender: 37% 1966 U nited States mg/lb. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events L osin L imbposture,passive stretch resistance,pain: PO O R. G eneralnursingcare,feeding: Spasticity severity brownurine (5/0) increase for2/3 onch lorz oxaz one;no placebo Timingofassessmentnotreported data provided;no F eedingdata provided Serious adverse events (resulting indeath ): aspirationpneumonia (1/2) L uisto Spasticity: 1 (flaccid)to 6 (marked) F A IR. A ctivities ofdaily living: N o improvementoneith er 35% treatment Drowsiness:15/17 vs. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics M cK inlay R andomiz ed A : Bacofen0. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events M cK inlay M uscle tone: A sh worth scale F A IR. C linicalglobalimpressionscale (moderate of Diz z iness: 6/20 vs. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events M eyth aler M uscle Tone: A sh worth scale F A IR. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics M onster R andomiz ed A : Dantrolene 50 mg Patients with 200 A ge: R ange from 35 to 50 years dependingonunderlying 96 crossovertrial Q IDtitrated to 100 mg spasticity of diagnosis 1974 Q ID various causes 147 F emale gender: A bout50% U. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events M onster O verallclinicalresponse (O C R ): measured by F A IR. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics N ogen R andomiz ed trial A : Dantrolene titrated Pediatricpatients 21 A ge range: 7 month s to 19 years 97 to 5. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events N ogen Spasticity: U nspecified meth od F A IR. Passive movementresistance: insignificant F atigue:5/14 vs. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics Sach ais R andomiz ed trial A :Baclofen,5 mgtid Inpatientor 166 M eanage=43 84 (outpatients)or10 mg outpatientadults 59% F emale 1977 U nited States tid (inpatients)titrated (18 years orolder) 106 92% W h ite to 70-80mg/day Spasticity 87% O utpatient M ulticenter secondary to M S B: Placebo (durationnot M ultiple Sclerosis C ombined inpatient specified) M eanDisease Duration-11 years and outpatientsetting 2-week titration,5- O ne-M onth Spasticity Stabiliz ation-70% week intervention Q uadraplegia -10/5 Paraplegia -30/33 H emiplegia -6/3 Previous muscle relaxantuse notreported Skeletal Muscle Relaxants Page 157 of 237 Final Report Update 2 Drug Effectiveness Review Project Evidence Table 4. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity A uth or M eth od ofO utcom e A ssessm entand O verallR ating and Y ear Tim ing ofA ssessm ent com m ents O utcom es A dverse Events Sach ais M entalState (Depression,Euph oria,Irritability); F A IR. Ph ysicianG lobalImpressions (5=marked; G lobalDisease Severity: -0. Placebo-controlled trials ofskeletalm uscle relaxants inpatients with spasticity Interventions A uth or Type ofStudy, Dose Enrolled Y ear Setting Duration Eligibility C riteria A nalyz ed PopulationC h aracteristics Sawa R andomiz ed A : Baclofen5mgTID Patients with 21 M eanage of49 formales and 36 forfemales 85 crossovertrial titrated to a maximum clinically definite 29% male 1979 of60mg M S ofch ronic 18 R ace notreported C anada myelopath y B: Placebo (presumed M S) C linically definite M S ofch ronicmyelopath y (presumed M S) Single center M eandurationofillness of14 years formales and 9 years for 21-days intervention, females 7-days wash out,21- days crossover Previous muscle relaxantuse notreported Sh eplan R andomiz ed trial A : Dantrolene titrated M ales with N otreported M eanage=47.

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Women Physical examination with subfertility are more likely to seek medical Always explain to the girl or woman what you are help (both in the formal and informal sector) going to do and ask a girl if she wants someone she and are prone to undergo curettage as ‘treat- trusts present at the examination trusted levitra 10 mg erectile dysfunction drugs and alcohol. They are also more likely to have weight (kg)/length × length (m) quality levitra 20mg erectile dysfunction due to zoloft. BMI <18 is had more sexual partners and therefore are at underweight and BMI >30 is obese. Infection of the uterus can cause intra- abdomen and/or thighs. Pituitary necrosis due to severe postpartum • Breasts: leaking of milk spontaneously or after hemorrhage (syndrome of Sheehan) causes lack careful expression (see how to do that in of pituitary hormones like follicle-stimulating Chapter 1). Failure to breastfeed is usually the first • External genitalia: clitoris, hymen, hair growth. In a girl with primary amenorrhea look for a • Abdominal pain. In non-pregnant women leakage charge, cervical abnormalities, cervical excita- of milk from the breast can point to hyper- tion, uterine size, pelvic mass. Then follows a progestational challenge test with norethis- No Yes terone 10mg daily for 10 days. If the patient bleeds, the presence of a uterus with sufficiently prepared ConsƟtuƟonal delay endometrium by estrogens and a competent outflow puberty Pregnancy test negĂƟve tract is confirmed. If the patient does not bleed, the Chronic illness or malnutriƟon next step is to give the combined oral contraceptive pill for one cycle which will cause a withdrawal Norethisterone 10 mg OD 10 days bleeding when a uterus and a functional outflow tract are present. No withdrawal bleeding usually means there is a defect in the endometrium, uterus No withdrawal bleeding Withdrawal bleeding or outflow tract and further investigations should be directed towards assessing these. Combined oral contracepƟve pill CAUSES OF AMENORRHEA See Table 1. No bleeding Bleeding Disorders of the ovary Absence of uterus Ovarian failure Gonadal dysgenesis imperforate hymen PCOS Gonadal dysgenesis can occur with normal XX and XY karyotypes, but the best known condition is Figure 2 Diagnostic work-up of primary amenorrhea Turner syndrome (45,X), whereby oocyte loss is accelerated. A typical girl with Turner syndrome • Ultrasound examination (see Chapter 1) (abdo- has short stature, webbed neck, shield chest, cubi- minal with full bladder or vaginal): uterus present, tus valgus and prepubertal external genitals. Because size of uterus, endometrium, ovarian size and the ovaries contain no primordial follicles, she will presence of follicles, tubo-ovarian mass, cysts, free not ovulate and menstruate and is infertile. In a girl with primary amenorrhea specifi- primary amenorrhea. Ultrasound examination can cally try to visualize the uterus as absence indicates be helpful to diagnose this condition, but is diffi- a congenital defect or chromosomal disorder. It might show a small uterus with no endome- trial lining and small ovaries with no primordial follicles. The progestational challenge test will Additional investigations cause no withdrawal bleeding, but the oral contra- • Pregnancy test ceptive pill will. Premature ovarian failure Premature ovarian failure means the loss of primor- dial follicles before age 40 years and the woman DIAGNOSTIC WORK-UP will enter menopause prematurely. Women can Most laboratories in low-resource settings lack the experience hot flushes, night sweats and a dry facilities to measure FSH, estradiol, thyroid- vagina due to epithelial atrophy. Premature ovarian stimulating hormone (TSH) and prolactin. These failure is usually idiopathic, but can be caused by hormonal essays are routinely used in the diagnosis radio- and chemotherapy, oophoritis or auto- of amenorrhea in high-resource clinical settings. Although the chance for preg- Therefore, this chapter will follow a more practical nancy is low, it does occur and patients who do not 86 Amenorrhea Pregnancy test negĂƟve Galactorrhea Yes No Recent use of depot Pregancy desired progesƟns Yes No Yes No BromocripƟne 2. Treatment is simple by contraceptives, preferably the oral contraceptive making a cruciate, a circular or elliptical incision in pill to prevent osteoporosis. It is important to talk the hymen and large amounts of chocolate-colored openly and repeatedly with the patient and if she fluid will come out5. Prophylactic antibiotics should allows, together with her partner, and counsel the be given before surgery. After evacuation of blood, couple on the low chances for pregnancy. These the edges of the hymen are excised to maintain an patients tend to visit a lot of different doctors and adequate opening5.

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