Maximizing ovarian function and fertility following chemotherapy in premenopausal patients: Is there a role for ovarian suppression?

As more premenopausal patients undergo fertility preserving cancer treatments, there is an increased need for fertility counseling and ovarian sparing strategies. Many patients receive gonadotoxic chemotherapeutic agents which can put them at risk of primary ovarian insufficiency or profoundly diminished ovarian reserve. Traditionally, estradiol and follicle stimulating hormone (FSH) values have been used to evaluate ovarian function but more recently, reproductive endocrinologists have been proponents of anti-mullerian hormone (AMH) as a validated measure of ovarian potential. While the gold standard for fertility preservation remains oocyte cryopreservation, data suggest there may be additional interventions that can mitigate the gonadotoxic effects of chemotherapeutic agents. The main objectives of this focused review were to quantify the risk of primary ovarian failure associated with the most common chemotherapies used in treatment of gynecologic cancers and to evaluate and recommend potential interventions to mitigate toxic effects on ovarian function. Chemotherapeutic agents can cause direct loss of oocytes and primordial follicles as well as stromal and vascular atrophy and the extent is dependent upon mechanism of action and age of the patient. The risk of ovarian failure is the highest with alkylating agents (42.2 %), anthracyclines (<10-34 % in patients under 40 years versus 98 % in patients aged 40-49), taxanes (57.1 %) and platinum agents (50 %). Multiple trials demonstrate that gonadotropin releasing hormone (GnRH) agonists, when administered concurrently with chemotherapy, may have protective effects, with more patients experiencing resumption of a regular menstruation pattern and recovering ovarian function more quickly post-treatment. Premenopausal patients receiving chemotherapy for the treatment of gynecologic cancers should receive adequate counseling on the potential adverse effects on their fertility. Although oocyte cryopreservation remains the gold standard for fertility preservation, there is some evidence to suggest that GNRH agonists could help maintain and preserve ovarian function and should be considered.

Oocyte Cryopreservation in Adolescent Women.

STUDY OBJECTIVE: To describe oocyte cryopreservation (OC) cycles in adolescent women (<20 years of age) performed at Society for Assisted Reproductive Technology member clinics in the United States from 2012 to 2016. DESIGN: Retrospective cohort study. SETTING: Not applicable. PARTICIPANTS: OC cycles from the Technology Clinic Outcome Reporting System database. INTERVENTIONS: OC cycles from 2012 to 2016 among adolescent women were compared with cycles in older women. MAIN OUTCOME MEASURE: Number of oocytes retrieved. RESULTS: From 2012 to 2016, OC cycles in women younger than 20 years of age accounted for 1.5% of OC cycles in all women. The absolute number has increased over the 5-year period, parallel to the increase in older women. OC cycles in adolescent women were most likely performed for fertility preservation for impending gonadotoxic treatment. The women were most likely to be non-Hispanic white and reside in the Northeast. Ten percent of the cycles were cancelled, most commonly for low response, compared with 6.6% of cycles in other age groups. There was no difference in mean oocytes retrieved in women younger than 20 years (n = 18.0) compared with women 20-29 years (n = 18.4). Complications, including ovarian hyperstimulation syndrome, were very rare. CONCLUSION: OC cycles in adolescent women are similar with regard to stimulation characteristics and oocyte yield to those in women of other age groups. There is, however, a higher likelihood of cancellation because of poor response.

Posaconazole concentrations after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Posaconazole is recommended for prophylaxis of fungal infections and for salvage therapy of invasive aspergillosis after stem cell transplantation. An impact of drug concentration on efficacy has been suggested. METHODS: In this study, we investigated serum levels of posaconazole in 262 samples from 64 allogeneic stem cell recipients. RESULTS: A high degree of interindividual variation was observed. Concentrations were significantly higher for male patients compared with female patients (median 570 and 426 ng/mL, respectively), but no differences for age or dosing groups (400 mg twice daily [BID] or 200 mg three times a day) could be detected. The predictive value of the first determined posaconazole concentration in steady state and of a concentration >500 and 700 ng/mL at any time was evaluated, compared with patients with a first level <300 ng/mL (mean 10.3%, median 0%). CONCLUSION: In patients receiving 400 mg BID, the mean rate of serum levels >500 ng/mL in subsequent determinations was higher, if the first serum concentration during steady state was >300 ng/mL (mean 61.1%, median 60%, P = 0.002) or >500 ng/mL (67.7%, median 75%, P = 0.002). Based on this retrospective analysis, a posaconazole serum concentration >500 ng/mL at any time point might also help to predict sufficient drug concentrations.

Low trough levels of tipranavir in a combination antiretroviral therapy of tipranavir/ritonavir and tenofovir require therapeutic drug monitoring.

The new non-peptidic protease inhibitor tipranavir is used boosted with ritonavir in a 500/200 mg bid scheme. Multiple drug interactions are described for both drugs because of their different action in CYP450 3A4 and p-glycoprotein. In this retrospective analysis of 22 patients during therapy with tipranavir/ritonavir (TPV) 500 mg/200 mg bid, we found significantly decreased TPV-trough levels in combination with tenofovir (15.32+/-5.22 microg/ml) in comparison to TPV trough levels without tenofovir (20.21+/-14.87 microg/ml). Therapeutic drug monitoring of TPV is recommended.

High performance liquid chromatographic method for the determination of HIV-1 protease inhibitor tipranavir in plasma of patients during highly active antiretroviral therapy.

A new high-performance liquid chromatographic method for the determination of tipranavir in human plasma is described. Quantitative recovery following liquid-liquid-extraction with diethylether from 100 microl of human plasma was achieved. Subsequently, the assay was performed with 67 mM potassium dihydrogen phosphate-acetonitrile as a mobile phase, a Phenomenex C 18 column and UV detection at 255 nm. Linear Standard curves were obtained for concentrations ranging from 2.5 to 400 microg/ml. The calculated intra- and inter-day coefficents of variation were below 7%.

Liquid chromatographic method for the determination of uridine in human serum.

To evaluate uridine levels in humans we developed a very sensitive and specific high-performance liquid chromatographic method for the determination of uridine in serum. We use techniques which are available in a standard analytical laboratory. Chromatographic analysis was carried out on a Phenomenex Aqua C18 5 micro 125A column protected by a guard cartridge system. Potassium dihydrogen phosphate buffer-acetonitrile was used as an eluent and oxypurinol as the internal standard. All sample preparation steps were done at 4 degrees C and the autosampler was cooled down to 4 degrees C. The calibration curve was linear throughout the calibration range from 0.25 to 100 micromol/l. This method was primarily established to evaluate uridine serum levels in patients with HIV infection since patients on highly active antiretroviral therapy (HAART) might develop metabolic disturbances that could lead to severe and fatal lactic acidosis due to mitochondrial toxicity. It is suggested that a limited or inadequate uridine supply is at least in part responsible for the onset of such deterioration.

Efavirenz plasma levels for the prediction of treatment failure in heavily pretreated HIV-1 infected patients.

OBJECTIVE: Efavirenz (EFV) plasma levels have been discussed as a predictor of treatment failure in HIV infected patients. The aim of this prospective, open-labeled, case-control study was to evaluate pretreated patients in regards to efavirenz plasma levels and efficacy of therapy. METHODS: Blood samples were obtained monthly from 33 patients receiving efavirenz in combination with other antiretroviral agents for at least 3 months. EFV plasma concentrations and potease inhibitor (PI) plasma levels were measured by high-performance liquid chromatography (HPLC). EFV plasma levels were correlated with efficacy. In patients with virologic failure genotypic resistance testing was performed. RESULTS: Mean efavirenz plasma levels (n = 240) of 33 patients were 3.119 +/- 2.497 ng/ml. There were no significant differences between median efavirenz plasma levels of 24 patients (72%) with a HIV-RNA < 20 copies/ml (2.168 ng/ml), 3 patients with HIV-RNA of 20 500 copies/ml (3.362 ng/ml), and 6 patients with a virologic failure (>500 copies/ml) (2.190 ng/ml) respectively. Efavirenz plasma levels below 1.000 ng/ml were found in 4/27 effective treated patients, and in 4/6 patients with virologic failure. In all patients with virologic failure multiple NRTI, NNRTI and PI mutations were found in genotypic resistance testing. CONCLUSION: An individual EFV plasma level below 1.000 ng/ml in one single measurement seems to be predictive of viral failure and the developement of genotypic resistance. Therapeutic drug monitoring of EFV might be helpful, especially in heavily pretreated patients, to reach long term sufficently effectiveness of therapy.

High-performance liquid chromatographic method for the determination of HIV-1 non-nucleoside reverse transcriptase inhibitor efavirenz in plasma of patients during highly active antiretroviral therapy.

A new high-performance liquid chromatographic method for the determination of efavirenz in human plasma is described. Quantitative recovery following liquid-liquid extraction with diethylether from 200 microl of human plasma was achieved. Subsequently, the assay was performed with 67 mM potassium dihydrogen phosphate-acetonitrile as a mobile phase, a XTerraRP 18 column protected with a Phenomenex C18 column and UV detection at 246 nm. Linear standard curves were obtained for concentrations ranging from 25 to 15,000 ng/ml. The calculated intra- and inter-day coefficients of variation were below 10%.

High-performance liquid chromatographic method for the simultaneous determination of HIV-1 protease inhibitors indinavir, saquinavir and ritonavir in plasma of patients during highly active antiretroviral therapy.

A new high-performance liquid chromatographic method for the simultaneous determination of indinavir, saquinavir and ritonavir in human plasma is described. Quantitative recovery following liquid-liquid extraction with diethyl ether from 500 microl of human plasma was achieved. Subsequently, the assay was performed with a linear gradient starting at 67 mM potassium dihydrogenphosphate-acetonitrile (65:35 to 40:60, v/v) as a mobile phase, a Phenomenex C18 column and UV detection at 240 and 258 nm, respectively. Linear standard curves were obtained for concentrations ranging from 75 to 20,000 ng/ml for indinavir, from 10 to 6000 ng/ml for saquinavir, and from 45 to 30,000 ng/ml for ritonavir. The calculated intra- and inter-day coefficients of variation were below 6%.