Chaque forme pharmaceutique présente ses propres avantages et inconvénients antibiotiques en ligne
mais n'ont pas d'effets néfastes pour l'organisme dans son ensemble.
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome
The Practice Committee of the American Society for Reproductive Medicine
American Society for Reproductive Medicine, Birmingham, Alabama
This Educational Bulletin discusses the pathophysiology, risk factors, clinical features, and management and pre-vention associated with ovarian hyperstimulation syndrome (OHSS). (Fertil Steril 2008;90:S188–93. 2008 byAmerican Society for Reproductive Medicine.)
Ovarian hyperstimulation syndrome (OHSS) is an exagger-
effects similar to those of OHSS that can be reversed with
ated response to ovulation induction therapy. The OHSS is
a specific antiserum ). Recent studies also indicate
typically associated with exogenous gonadotropin stimula-
that hCG increases VEGF expression in human granulosa
tion and is only rarely observed with use of other agents
cells and raises serum VEGF concentrations (). Numer-
(clomiphene citrate [CC] and gonadotropin-releasing hor-
ous other factors may be involved, acting directly or indi-
mone [GnRH]). Clinicians who prescribe ovulation-inducing
rectly via VEGF, including angiotensin II, insulin-like
agents must be prepared to recognize and manage OHSS
growth factor 1 (IGF-1), epidermal growth factor (EGF),
transforming growth factors (TGF) a and b, basic broblastgrowth factor (BFGF), platelet-derived growth factor
OHSS is a self-limiting disorder that usually resolves spon-
(PDGF), interleukin-1b (IL-1b), and interleukin-6 (IL-6)
taneously within several days, but may persist for longer du-
rations, particularly in conception cycles. The syndrome hasa broad spectrum of clinical manifestations, from mild illnessneeding only careful observation to severe disease requiring
hospitalization and intensive care. This guideline will discuss
The following factors increase the risk independently for
the pathophysiology of OHSS and its risk factors, clinical
developing OHSS ):
features, management, and prevention.
young age low body weight
polycystic ovary syndrome (PCOS)
The hallmark of OHSS is an increase in capillary permeabil-
higher doses of exogenous gonadotropins
ity resulting in a fluid shift from the intravascular space to
high absolute or rapidly rising serum E2 levels
third space compartments (Factors that have been im-
previous episodes of OHSS
plicated in the process include:
In addition, risk rises with the number of developing ovar-
increased secretion or exudation of protein-rich fluid
ian follicles (and the number of oocytes retrieved in
from enlarged ovaries or peritoneal surfaces ()
assisted reproductive technology (ART) cycles (
increased follicular fluid levels of prorenin and renin
Risk increases when higher or repeated doses of exogenous
hCG are administered in superovulation and ART cycles
angiotensin-mediated changes in capillary permeability
(for ovulation induction or luteal phase support) and
decreases when exogenous P, rather than hCG, is used to sup-
Vascular endothelial growth factor (VEGF), also known as
port the luteal phase ). Pregnancy increases the likelihood,
vascular permeability factor, has emerged as one of the fac-
duration, and severity of OHSS symptoms.
tors most likely involved in the pathophysiology of OHSS). VEGF is an angiogenic cytokine that is a potent stimu-lator of the vascular endothelium and appears to play an inte-
gral role in follicular growth, corpus luteum function, and
The OHSS has traditionally been classified as mild, moder-
ovarian angiogenesis. The VEGF levels correlate with the
ate, or severe. However, the clinical symptoms and signs of
severity of OHSS (and recombinant VEGF produces
OHSS exhibit a continuum of scope and severity that de-fies attempts at specific classification or staging.
Mild manifestations of OHSS are relatively common and
Reviewed June 2008.
Received July 14, 2003; revised and accepted July 14, 2003.
No reprints will be available.
transient lower abdominal discomfort
Correspondence to: Practice Committee, American Society for Reproduc-
tive Medicine, 1209 Montgomery Highway, Birmingham, Alabama35216.
Fertility and Sterility Vol. 90, Suppl 3, November 2008
Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
Strenuous physical activity should be avoided as risk of
abdominal distention (observed in up to a third of super-
ovarian torsion increases when the ovaries are signifi-
ovulation cycles) (
cantly enlarged. Light physical activity should bemaintained to the extent possible. Strict bed rest is un-
Onset of symptoms typically occurs soon after ovulation
warranted and may increase risk of thromboembolism.
(in superovulation cycles) or after oocyte retrieval in ART
Weight should be recorded daily, as well as the fre-
cycles, but it may be delayed.
quency and/or volume of urine output. Weight gain of
Progression of illness is recognized when symptoms per-
R2 pounds per day or decreasing urinary frequency
sist, worsen, or include ascites that may be demonstrated
should prompt repeated physical examination, ultra-
by increasing abdominal girth or ultrasound evaluation. Seri-
sound, and laboratory evaluation to include hematocrit,
ous illness exists when pain is accompanied by one or more of
electrolytes, and serum creatinine.
Pregnant patients with OHSS must be monitored very
closely because risk of progressing to severe disease is
rapid weight gain
particularly high for those further stimulated by rapidly
rising serum concentrations of hCG.
hemodynamic instability (orthostatic hypotension,
In ART cycles, it may be necessary to consider cryopre-
serving all embryos and deferring transfer to a subse-
respiratory difficulty (tachypnea)
quent cycle after symptoms have completely resolved.
Although pregnancy rates in frozen ET cycles are gener-
ally lower than in fresh cycles, this approach may reduce
Hypotension results from extravasation of protein-rich
the risk for developing severe OHSS without a marked
fluid and contraction of the vascular volume, oliguria/anuria
decrease in pregnancy rates per cycle
from reduced renal perfusion due to decreased vascular vol-ume and/or tense ascites, and pulmonary compromise from
an elevated diaphragm and/or hydrothorax. Risk of thrombo-
Serious illness requiring hospitalization is relatively uncom-
embolism is increased as a result of hemoconcentration, di-
mon but by no means rare. Hospitalization may be required
minished peripheral blood flow, and inactivity due to
based on severity of symptoms, analgesic requirements,
abdominal distension and pain. Life-threatening complica-
and other social considerations (availability of responsible
tions of OHSS include renal failure, adult respiratory distress
adult supervision, support, and assistance with child care).
syndrome (ARDS), hemorrhage from ovarian rupture, andthromboembolism ().
Given the scope and severity of symptoms and the poten-
tial for complications, most women with OHSS who are se-riously ill merit hospitalization for more careful monitoring
and aggressive treatment. No one symptom or sign is an ab-
solute indication, but hospitalization should be considered
Patients with mild manifestations of OHSS can be managed
when one or more of the following are present:
on an outpatient basis. Treatment usually requires only oral
severe abdominal pain or peritoneal signs
analgesics and counseling regarding the signs and symptoms
intractable nausea and vomiting that prevents ingestion
of progressing illness. Intercourse is best avoided as it may be
of food and adequate fluids
painful and may increase the risk of ovarian rupture.
severe oliguria or anuria
Treatment of worsening OHSS typically requires anti-
emetics and more potent analgesics. Most patients still can
dyspnea or tachypnea
be effectively managed and monitored on an outpatient basis,
hypotension (relative to baseline), dizziness, or syncope
but they require more careful evaluation including frequent
severe electrolyte imbalance (hyponatremia, hyperkale-
physical and ultrasound examinations (to detect increasing
ascites), daily weight measurements, and serial laboratory
determinations of hematocrit, electrolytes, and serum creati-
abnormal liver function tests
nine. Careful monitoring is essential and should include at
Laboratory findings in women with serious illness result-
least daily communication, if not examination, to ensure
ing from OHSS include (
that progression to more severe disease is promptly recog-nized.
hemoconcentration (hematocrit >45%) leukocytosis (white blood cell count >15,000)
Recommendations for the outpatient management of
electrolyte imbalances (hyponatremia: sodium <135
persistent and worsening OHSS include:
mEq/L; hyperkalemia: potassium >5.0 mEq/L)
Oral fluid intake should be maintained at no less than 1 L
elevated liver enzymes
per day; any of the commercially available electrolyte-
decreased creatinine clearance (serum creatinine >1.2;
supplemented drinks is preferable to other beverages.
creatinine clearance <50 mL/min)
Fertility and Sterility
Recommendations for the evaluation and monitoring of
Albumin (25%) in doses of 50–100 g, infused over 4
hospitalized patients with OHSS include the following:
hours and repeated at 4- to 12-hour intervals as neces-sary, is an effective plasma expander when infusion of
vital signs (every 2–8 hours, according to clinical status)
normal saline fails to achieve or maintain hemodynamic
weight (recorded daily)
stability and adequate urine output. In general, albumin
complete physical examination (daily, avoiding biman-
is the preferred plasma expander (although others
ual examination of the ovaries due to risk of ovarian rup-
(e.g., mannitol, fresh frozen plasma) may be used. Dex-
tran has been associated with development of adult
abdominal circumference (at the navel, recorded daily)
respiratory distress syndrome (ARDS) and is best
monitoring of fluid intake and output (daily, or more of-
Treatment with diuretics (e.g., furosemide, 20 mg IV)
ultrasound examination (ascites, ovarian size), repeated
may be considered after an adequate intravascular vol-
as necessary to guide management or paracentesis (see
ume has been restored (hematocrit <38%). Premature
or overzealous use of diuretics will aggravate hypovole-
chest X-ray and echocardiogram (when pleural or peri-
mia, and hemoconcentration, thereby increasing risk of
cardial effusion is suspected), repeated as necessary
pulse oximetry (for patients with symptoms of pulmo-
Intravenous fluid administration should be sharply
curtailed and oral fluid intake increased when there is
complete blood count (daily, or more often as needed to
evidence that the syndrome is resolving, generally her-
guide fluid management)
alded by improving symptoms and onset of a brisk
serum creatinine or creatinine clearance, urine specific
Hyperkalemia is associated with risk of cardiac dys-
gravity, repeated as necessary
rhythmias. Acute management involves treatments that
liver enzymes, repeated as necessary
move potassium into the intracellular space (insulin
Careful and frequent re-evaluation of the hospitalized
and glucose, sodium bicarbonate, albuterol) or protect
patient with severe OHSS is essential. Complaints of increas-
the heart from the effects of elevated potassium levels
ing abdominal pain and distension demand immediate atten-
(calcium gluconate). Electrocardiographic manifesta-
tion, remaining mindful that pain and ascites can easily mask
tions of hyperkalemia (prolonged PR and QRS intervals,
ovarian rupture and acute intra-abdominal hemorrhage. Serial
ST segment depression, tall peaked T waves) indicate
clinical and laboratory evaluations provide the means to mon-
the need for immediate treatment with calcium gluco-
itor progression of illness, to judge the response to treatment,
nate. Kayexelate is a cation exchange resin that removes
and to recognize evidence of resolution.
potassium from the body but works more slowly (onsetof action 1–2 hours); it may be administered orally orrectally as a retention enema.
Hospitalized patients require IV fluid management to addressthe acute need for volume expansion while also considering
the marked increase in vascular permeability that accom-
Ultrasound-guided paracentesis may be indicated for patients
panies severe OHSS. Renal and pulmonary function must
with ascites that causes pain, compromised pulmonary func-
be carefully monitored. Guidelines for fluid management
tion (e.g., tachypnea, hypoxia, hydrothorax) (or oliguria/
for patients hospitalized with severe illness relating to
anuria that does not improve with appropriate fluid manage-
OHSS include the following (
ment. A transvaginal or transabdominal approach may be
Strict monitoring of fluid intake and urine output is
used, under gentle ultrasound guidance (The optimal
essential until symptoms improve or diuresis begins.
volume of fluid that should be removed on any one occasion,
Oral fluid intake should be carefully recorded and lim-
and over what interval of time, is not well established.
ited to those amounts necessary to maintain the patient's
Whereas rapid removal of large volumes of ascitic fluid has
been observed to trigger dangerous compensatory fluid shifts
Rapid initial hydration may be accomplished with a bo-
in elderly patients with malignant ascites, the risk of such
lus of IV fluid (500–1,000 mL). Thereafter, fluids should
complications in young, otherwise healthy women with
be administered judiciously, in the volumes necessary to
OHSS is generally small. Nevertheless, it is prudent to re-
maintain adequate urine output (>20–30 mL/h) and
move fluid at a deliberate pace until the desired effect is
reverse hemoconcentration. Five percent dextrose in
achieved, while carefully monitoring the patient's response.
normal saline is preferable to lactated Ringer's solution,
Serial paracentesis may be required to maintain adequate re-
given the tendency to hyponatremia. Correction of hy-
nal and pulmonary function. Severe ascites may be associated
povolemia, hypotension, and oliguria has highest prior-
with hydrothorax, most commonly on the right, resulting
ity, accepting that fluid administration may contribute to
from transfer of abdominal fluid to the chest via the thoracic
the accumulation of ascites.
duct. Paracentesis will generally be effective in resolving
ASRM Practice Committee
Ovarian hyperstimulation syndrome
Vol. 90, Suppl 3, November 2008
hydrothorax and thoracentesis may be reserved for those with
LH surge to promote final oocyte maturation and induce
bilateral or severe pleural effusions that persist ().
ovulation ). This approach would be useful only in cyclesnot involving previous down-regulation with longer term ag-
Thromboembolism is a life-threatening complication of
onist treatment or use of a GnRH antagonist (e.g., ganirelix,
severe OHSS, and prophylactic measures are warranted.
Full-length venous support stockings are recommended, andprophylactic heparin therapy (5,000 U SC, every 12 hours)
Regardless whether hCG or a GnRH agonist is adminis-
should be seriously considered. The use of an intermittent
tered at midcycle, the use of exogenous P (e.g., 50 mg P in
pneumatic compression device is prudent when symptoms
oil IM, 100 mg P vaginal suppositories, or 8% P vaginal
prevent ambulation and confine the patient to bed. Signs
gel, daily) for luteal phase support rather than supplemental
and symptoms suggesting thromboembolism demand prompt
doses of hCG, may further reduce risks of OHSS (
additional diagnostic measures (arterial blood gas measure-
When symptoms of OHSS emerge even before administra-
ments, ventilation/perfusion scan) and therapeutic anticoagu-
tion of hCG, cycle cancellation and less aggressive stimula-
lation when the diagnosis is confirmed or strongly suspected.
tion in a subsequent cycle should be seriously considered.
Intensive care may be required for management of
Although evidence indicates that meticulous follicle aspi-
thromboembolic complications, renal failure, or pulmonary
ration will reduce corpus luteum P production, it cannot be
compromise that does not respond to supportive care and
relied on to prevent development or progression of OHSS
paracentesis. Renal failure will often respond to low-dose do-
in ART cycles ).
pamine therapy (0.18 mg/kg/h) that will dilate renal vessels
Prophylactic IV administration of 25% albumin (20–50 g)
and increase renal blood flow ). Invasive monitoring of
at time of oocyte retrieval has been suggested as a means to
central venous pressure or pulmonary capillary wedge pres-
reduce risk of OHSS when E
sure and even short-term dialysis may be required. Pulmo-
2 levels are markedly elevated
or there is history of a previous episode of OHSS
nary intensive care may involve oxygen supplementation,
Studies of its efficacy have had mixed results, and albumin
thoracentesis, and assisted ventilation when more conserva-
treatment risks exacerbation of ascites, allergic reactions,
tive measures fail. Patients with severe OHSS who may re-
and virus/prion transmission (However, a recent
quire surgery for a ruptured ovarian cyst with hemorrhage,
meta-analysis of five randomized controlled trials demon-
torsion, or an ectopic pregnancy present a unique challenge
strated that prophylactic albumin administration significantly
for the anesthesiologist who is unlikely to be familiar with
reduced risk of developing OHSS (odds ratio [OR] 0.28, 95%
the pathophysiology of the syndrome and must be quickly ed-
confidence interval [CI] 0.11, 0.73); albumin infusion may be
ucated to minimize the additional risks involved ).
expected to prevent one case of severe OHSS for every 18women at risk who are treated ).
The keys to preventing OHSS are experience with ovulationinduction therapy and recognition of risk factors for OHSS.
Ovulation induction regimens should be highly individual-
Experience with ovulation induction therapy and knowl-
ized, carefully monitored, and use the minimum dose and du-
edge of OHSS pathophysiology, risk factors, and clini-
ration of gonadotropin therapy necessary to achieve the
cal features are key to preventing and managing OHSS.
Mild manifestations of OHSS are fairly common, occur-
ring in up to a third of exogenous gonadotropin-induced
Caution is indicated when any of the following indicators
for increasing risk of OHSS are present:
Worsening symptoms of OHSS can still usually be man-
rapidly rising serum E2 levels
aged on an outpatient basis, but frequent monitoring and
an E2 concentration in excess of 2,500 pg/mL
evaluation are essential.
the emergence of a large number of intermediate sized
Serious illness resulting from OHSS is much less com-
follicles (10–14 mm)
mon, but it can be life-threatening.
Hospitalization may be necessary for patients with seri-
Withholding further gonadotropin stimulation and delaying
ous illness resulting from OHSS.
hCG administration until E2 levels plateau or decrease signif-icantly can reduce risks of OHSS Available evidencesuggests that such ‘‘coasting'' does not adversely affect out-come in IVF cycles unless it is prolonged (>3 days) ).
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Intravenous albumin for the prevention of severe ovarian hyperstimula-
Fertility and Sterility
7th Workshop on Recent Issues in Bioanalysis Poster List Tuesday April 9 Posters Poster T01: "Validation of a Dried Blood Spot Boanalytical Method for Perampanel Analysis in Pediatric Studies" Poster Presenter: Dr. Luca Matassa (Eisai, Woodcliff Lake, NJ, USA) Introduction: Perampanel is a first-in-class, orally administered, highly selective non-competitive AMPA-type glutamate receptor antagonist, developed by EISAI for epilepsy. A DBS-LC-MS/MS method has been developed and validated in order to analyse perampanel in heparinised blood samples from paediatric studies. Dried blood spots (DBS) have been shown to be a useful means of collecting, storing and shipping blood samples for quantitative drug analysis which provides advantages over conventional plasma collection. Moreover, due to low sample volume that DBS uses, it is a method of choice when it is comes to paediatric studies. Methods: A 20 uL dried blood spot on FTA DMPK A card is punched (6mm punch) and the subsample is solubilized by shaking in 150 uL of 90/10 methanol water containing internal standard (IS) stable label peramapanel. An aliquot of the solution is diluted with an equal volume of 50/50 methanol/water, centrifuged at 4C for 5 min prior to injecting 10uL on a reverse phase column (Chromolith RP18e 100x3mm) at 40C under gradient conditions. The detector was a Sciex API5500 Qtrap operated in positive ion ionspray mode. Quantitation was achieved monitoring precursor/product ions for analyte and IS (350/219 m/z perampanel; 356/219 IS) at retention time 2.5 minutes using 1/x2 linear weighted regression. Result: A full validation according to FDA and EMA guidance was conducted in human blood. Assay linearity was demonstrated over 7 validation runs with R-squared greater than 0.995. The intra-run accuracy and precision was between 95.2 -107.6% and 3.1-12.6%, respectively, at four concentration levels (LLQ, low QC, mid QC, high QC) demonstrating the repeatability of the analytical method from 1 to 500 ng/mL. The matrix factor in 6 lots of control blood was 1.0 for analyte and IS. Control blank matrix showed no interference at the LLQ. Punch tool carryover and autoinjector carryover were not found to impact assay performance. Analyte and IS recovery was 80% across all 3 QC levels with imprecision less than 5%. A 2-fold dilution factor was validated. The specificity of the method for perampanel at the LLOQ in presence of 10 other commonly used AEDs, individual y or pooled all together, (valproic acid, phenobarbital, lamotrigine, topiramate, oxcarbazepine, carbamazepine, levetiracetam, zonisamide, phenytoin, primidone) was demonstrated. A blood/plasma ratio of 0.88 was determined, allowing the correlation between blood and previous study plasma results. Short term autosample perampanel extract stability and perampanel stability in blood was demonstrated. Perampanel long term stability on DBS was demonstrated for 363 days at room temperature. Novel Aspect / Conclusion: The fully validated DBS-LC-MS/MS method was successfully applied to analysis of paediatric study clinical samples. Poster T02: "Unexpected Results for Sample Col ection and Handling Stability Assessment for Sumatriptan in Human Plasma" Poster Presenter: Ginny James (Celerion, Lincoln, Nebraska, USA) Introduction: Determination of sample col ection and handling stability (SCHS) is a requirement for validation of bioanalytical methods. SCHS of sumatriptan for 120 minutes did not meet pre-defined acceptance criteria. As sumatriptan was stable in plasma for 23 hours at ambient temperature, it was hypothesized that partitioning of sumatriptan between plasma and red blood cells was not immediate and was impacting the results of the early time points. Methods: Whole blood was fortified with sumatriptan at 0.150 and 100 ng/mL for target plasma concentrations of approximately 0.300 and 200 ng/mL. The samples were incubated in an ice-water bath, at ambient temperature, and at 37°C for multiple time points between 0 and 120 minutes. At each time point, samples were centrifuged, and the plasma layer was immediately frozen at -20°C. For samples in an ice-water bath for 30 minutes, the red cell fraction was also stored at -20°C for testing. The collected plasma samples were analyzed using a validated method for the quantitation of sumatriptan in human plasma. Red blood cel s were analyzed with the same chromatographic and instrument conditions after a protein crash of the cellular material.
CURRENT DRUG THERAPY EDUCATIONAL OBJECTIVE: Readers will prescribe antidepressant drugs more confidently on the basis CREDIT of the characteristics of the patient and the various drugs ELIZABETH SHULTZ, DO DONALD A. MALONE, JR., MD Department of Psychiatry and Psychology, Chair, Department of Psychiatry and Psychology, Cleveland Clinic; Clinical Instructor, Cleveland Cleveland Clinic; Professor, Cleveland Clinic Lerner