L-Citrulline Supplementation Improves Arterial Blood Flow and Muscle Oxygenation during Handgrip Exercise in Hypertensive Postmenopausal Women.

Endothelial dysfunction decreases exercise limb blood flow (BF) and muscle oxygenation. Acute L-Citrulline supplementation (CIT) improves muscle tissue oxygen saturation index (TSI) and deoxygenated hemoglobin (HHb) during exercise. Although CIT improves endothelial function (flow-mediated dilation [FMD]) in hypertensive women, the impact of CIT on exercise BF and muscle oxygenation (TSI) and extraction (HHb) are unknown. We examined the effects of CIT (10 g/day) and a placebo for 4 weeks on blood pressure (BP), arterial vasodilation (FMD, BF, and vascular conductance [VC]), and forearm muscle oxygenation (TSI and HHb) at rest and during exercise in 22 hypertensive postmenopausal women. Compared to the placebo, CIT significantly (p < 0.05) increased FMD (Δ-0.7 ± 0.6% vs. Δ1.6 ± 0.7%) and reduced aortic systolic BP (Δ3 ± 5 vs. Δ-4 ± 6 mmHg) at rest and improved exercise BF (Δ17 ± 12 vs. Δ48 ± 16 mL/min), VC (Δ-21 ± 9 vs. Δ41 ± 14 mL/mmHg/min), TSI (Δ-0.84 ± 0.58% vs. Δ1.61 ± 0.46%), and HHb (Δ1.03 ± 0.69 vs. Δ-2.76 ± 0.77 µM). Exercise BF and VC were positively correlated with improved FMD and TSI during exercise (all p < 0.05). CIT improved exercise artery vasodilation and muscle oxygenation via increased endothelial function in hypertensive postmenopausal women.

Endothelial dysfunction influences augmented aortic hemodynamic responses to metaboreflex activation in postmenopausal women.

PURPOSE: Postmenopausal women experience augmented aortic hemodynamic responses to isometric handgrip (IHG) exercise and metaboreflex activation post-exercise muscle ischemia (PEMI). Relationships between endothelial function brachial artery flow-mediated dilation (FMD) and aortic stiffness carotid-femoral pulse wave velocity (cfPWV) with aortic pulsatile hemodynamics during IHG and PEMI have not been determined. The relationships between aortic hemodynamic responses to PEMI were evaluated. METHODS: Aortic blood pressure (BP), wave reflection, and pressure of forward (Pf) and backward (Pb) waves were measured using arterial tonometry at rest, IHG at 30% maximal force, and PEMI in 30 (15/group) postmenopausal women with low (≤ 4.5%) and normal (≥ 5.5%) FMD. Hemodynamic responses were analyzed as the change (Δ) from rest to the last minute of IHG and PEMI. RESULTS: Brachial and aortic systolic BP (SBP) responses to IHG were higher in the low vs normal FMD group (P < 0.05). Aortic SBP (Δ20 ± 8 vs Δ11 ± 7 mmHg), pulse pressure (PP) (Δ12 ± 8 vs Δ6 ± 4 mmHg), augmented pressure (AP) (Δ5 ± 3 vs Δ2 ± 2 mmHg), and Pb (Δ6 ± 4 vs Δ3 ± 2 mmHg) responses to PEMI were greater (P < 0.05) in women with low vs. normal FMD. FMD was negatively correlated with aortic SBP, PP, AP, and Pb (P < 0.05) responses to PEMI. cfPWV was not correlated with responses to PEMI. CONCLUSION: Endothelial dysfunction relates to augmented aortic pulsatile load during metaboreflex activation, which may increase cardiovascular risk in postmenopausal women.

Endothelial and exercise vasodilation are reduced in postmenopausal females with obesity versus lean and overweight.

BACKGROUND: Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories. METHODS: Participants were grouped by body mass index (BMI) into LN (BMI 18.5-24.9 kg/m2; n = 11), OW (BMI 25.0-29.9 kg/m2; n = 15), and OB (BMI 30.0-39.9 kg/m2; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises. RESULTS: Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -0.386, P = 0.015, FA-VC: r = -0.456, P = 0.004). CONCLUSION: Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females.

L-Citrulline supplementation attenuates aortic pressure and pressure waves during metaboreflex activation in postmenopausal women.

Postmenopausal women have augmented pressure wave responses to low-intensity isometric handgrip exercise (IHG) due to an overactive metaboreflex (postexercise muscle ischaemia, PEMI), contributing to increased aortic systolic blood pressure (SBP). Menopause-associated endothelial dysfunction via arginine (ARG) and nitric oxide deficiency may contribute to exaggerated exercise SBP responses. L-Citrulline supplementation (CIT) is an ARG precursor that decreases SBP, pulse pressure (PP) and pressure wave responses to cold exposure in older adults. We investigated the effects of CIT on aortic SBP, PP, and pressure of forward (Pf) and backward (Pb) waves during IHG and PEMI in twenty-two postmenopausal women. Participants were randomised to CIT (10 g/d) or placebo (PL) for 4 weeks. Aortic haemodynamics were assessed via applanation tonometry at rest, 2 min of IHG at 30 % of maximal strength, and 3 min of PEMI. Responses were analysed as change (Δ) from rest to IHG and PEMI at 0 and 4 weeks. CIT attenuated ΔSBP (−9 ± 2 v. −1 ± 1 mmHg, P = 0·006), ΔPP (−5 ± 2 v. 0 ± 1 mmHg, P = 0·03), ΔPf (−6 ± 2 v. −1 ± 1 mmHg, P = 0·01) and ΔPb (−3 ± 1 v. 0 ± 1 mmHg, P = 0·02) responses to PEMI v. PL. The ΔPP during PEMI was correlated with ΔPf (r = 0·743, P < 0·001) and ΔPb (r = 0·724, P < 0·001). Citrulline supplementation attenuates the increase in aortic pulsatile load induced by muscle metaboreflex activation via reductions in forward and backward pressure wave amplitudes in postmenopausal women.

Effect of Combined Grape Seed Extract and L-Citrulline Supplementation on Hemodynamic Responses to Exercise in Young Males.

Grape seed extract (GSE) or L-citrulline supplement has been known to increase nitric oxide (NO) bioavailability and enhance endothelial-mediated vasodilation. Accordingly, to examine the additive benefits of combination of the two supplementations on hemodynamic responses to dynamic exercise, young, healthy males were recruited for this study. Effects of 7 days of 1) GSE + L-citrulline, 2) GSE, 3) L-citrulline, and 4) placebo supplementation on systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), cardiac output, total vascular conductance (TVC), and oxygen (O2) consumption were examined at rest and during cycling exercise. Compared with placebo, GSE, L-citrulline, and combined supplementations did not reduce SBP, DBP, and MAP, while cardiac output (placebo; 23.6 ± 1.3 L/min, GSE; 25.7 ± 1.1 L/min; L-citrulline, 25.2 ± 1.2 L/min; GSE + L-citrulline; 25.3 ± 0.9 L/min) and TVC (placebo; 234.7 ± 11.3 ml/min/mmHg, GSE; 258.3 ± 10.6 ml/min/mmHg; L-citrulline, 255.2 ± 10.6 ml/min/mmHg; GSE + L-citrulline; 260.4 ± 8.9 ml/min/mmHg) were increased at only the 80% workload (p < 0.05). Compared with placebo and L-citrulline, GSE and combined supplementations had a reduction in VO2 across workloads (p < 0.05). However, there was no additive benefits on these variables. We conclude that supplementation with GSE, L-citrulline, and combined supplementations increased cardiac output due partially to decreased vascular resistance. Our findings suggest that GSE may act as an ergogenic aid that can improve O2 delivery to exercising muscles.

Combined Citrulline and Glutathione Supplementation Improves Endothelial Function and Blood Pressure Reactivity in Postmenopausal Women.

Postmenopausal women (PMW) may experience endothelial dysfunction associated with arginine (ARG) deficiency relative to asymmetric dimethylarginine (ADMA) caused by oxidative stress. Endothelial dysfunction contributes to increased blood pressure (BP) responsiveness to sympathoexcitation induced by the cold pressor test (CPT). We investigated the effects of citrulline alone (CIT) and combined with the antioxidant glutathione (CIT+GSH) on vascular function. Forty-four healthy PMW were randomized to CIT (6 g), CIT+GSH (2 g + 200 mg: Setria®) or placebo (PL) for 4 weeks. Brachial artery flow-mediated dilation (FMD), aortic stiffness (pulse wave velocity, PWV), brachial and aortic BP reactivity to CPT, and serum fasting blood glucose (FBG), ARG, and ARG/ADMA ratio were measured. Baseline FBG was higher in CIT+GSH vs. PL. FMD increased after CIT+GSH vs. PL (p < 0.05). CIT and CIT+GSH increased ARG/ADMA (p < 0.05), but did not affect aortic PWV. CIT+GSH attenuated the brachial and aortic systolic BP and mean arterial pressure (MAP) responses to CPT vs. PL and CIT (p < 0.05). The improvements in FMD were related to baseline FMD (r = -0.39, p < 0.05) and aortic MAP response to CPT (r = -0.33, p < 0.05). This study showed that CIT+GSH improved FMD and attenuated systolic BP and MAP reactivity in PMW. Although CIT increased ARG/ADMA, it did not improve FMD in healthy PMW.

Menopause influences aortic pulse pressure and pressure wave responses to metaboreflex activation in women.

OBJECTIVE: Postmenopausal women (post-MW) have greater risk of heart failure due to aortic pulsatile overload on the left ventricle associated with increased backward wave pressure (Pb). Post-MW have exaggerated peripheral blood pressure (BP) response to exercise mediated by metaboreflex (postexercise muscle ischemia [PEMI]) overactivation. Increased forward wave pressure (Pf) and Pb are determinants of aortic pulse pressure (PP) during isometric handgrip exercis (IHG) in young adults. We hypothesized that aortic PP and pressure wave responses to PEMI are augmented in nonhypertensive post-MW compared with premenopausal women (pre-MW). METHODS: Aortic BP, Pf, Pb, and reflection magnitude were assessed at rest and during IHG and PEMI by applanation tonometry in 15 pre-MW and 16 post-MW. RESULTS: Aortic systolic BP during PEMI similarly increased in both groups. The increase in diastolic BP was lower in post-MW (post-MW Δ6 ± 2 vs pre-MW Δ11 ± 2 mm Hg, P < 0.05). Aortic PP (post-MW Δ8 ± 2 vs pre-MW Δ3 ± 2), Pf (post-MW Δ6 ± 1 vs pre-MW Δ0 ± 1), and Pb (post-MW Δ5 ± 1 vs pre-MW Δ2 ± 1) augmented during PEMI in post-MW ( P < 0.05 for all), but not in pre-MW. Reflection magnitude increased during PEMI only in pre-MW (pre-MW Δ7 ± 2 vs post-MW Δ-1 ± 2, P < 0.05) due to concurrent increases in Pf and Pb in post-MW. CONCLUSIONS: Even in nonhypertensive postmenopausal women, increases in Pf and Pb and decrease in aortic DBP are important factors that contribute to the augmented aortic PP response to PEMI.

Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women.

Aging and menopause are associated with decreased nitric oxide bioavailability due to reduced L-arginine (L-ARG) levels contributing to endothelial dysfunction (ED). ED precedes arterial stiffness and hypertension development, a major risk factor for cardiovascular disease. This study investigated the effects of L-citrulline (L-CIT) on endothelial function, aortic stiffness, and resting brachial and aortic blood pressures (BP) in hypertensive postmenopausal women. Twenty-five postmenopausal women were randomized to 4 weeks of L-CIT (10 g) or placebo (PL). Serum L-ARG, brachial artery flow-mediated dilation (FMD), aortic stiffness (carotid-femoral pulse wave velocity, cfPWV), and resting brachial and aortic BP were assessed at 0 and 4 weeks. L-CIT supplementation increased L-ARG levels (Δ13 ± 2 vs. Δ−2 ± 2 µmol/L, p < 0.01) and FMD (Δ1.4 ± 2.0% vs. Δ−0.5 ± 1.7%, p = 0.03) compared to PL. Resting aortic diastolic BP (Δ−2 ± 4 vs. Δ2 ± 5 mmHg, p = 0.01) and mean arterial pressure (Δ−2 ± 4 vs. Δ2 ± 6 mmHg, p = 0.04) were significantly decreased after 4 weeks of L-CIT compared to PL. Although not statistically significant (p = 0.07), cfPWV decreased after L-CIT supplementation by ~0.66 m/s. These findings suggest that L-CIT supplementation improves endothelial function and aortic BP via increased L-ARG availability.

Acute Citrulline Blunts Aortic Systolic Pressure during Exercise and Sympathoactivation in Hypertensive Postmenopausal Women.

PURPOSE: Hypertensive postmenopausal women (PMW) have exaggerated exercise systolic blood pressure (SBP) due to impaired functional sympatholysis. l-Citrulline (CIT) supplementation attenuates aortic SBP responses to cold pressor test (CPT)-induced vasoconstriction in young men. We hypothesized that acute CIT ingestion would attenuate aortic SBP and leg hemodynamic responses during exercise and CPT (EX + CPT). METHODS: Fifteen hypertensive PMW (61 ± 7 yr) were randomly assigned to consume either 6 g of CIT or placebo (PL) separated by a minimum 3-d washout phase. Brachial and aortic blood pressure, femoral artery blood flow (FBF), and vascular conductance (FVC) were measured at rest and during 5 min of unilateral plantarflexion exercise with a CPT applied during minutes 4 and 5. RESULTS: No differences between conditions were found in FBF, FVC, and brachial and aortic blood pressure at rest and during exercise alone. Changes in brachial SBP (CIT vs PL, 29 ± 12 vs 40 ± 10 mm Hg) and mean arterial pressure (CIT vs PL, 21 ± 10 vs 33 ± 11 mm Hg), and aortic SBP (CIT vs PL, 27 ± 11 vs 38 ± 9 mm Hg) and mean arterial pressure (CIT vs PL, 23 ± 9 vs 33 ± 11 mm Hg) to EX + CPT were lower in the CIT versus PL condition (P < 0.05). FBF, FVC, and functional sympatholysis (%ΔFVC) were not significantly different between conditions. CONCLUSIONS: Acute CIT ingestion attenuated aortic SBP response to exercise and cold-induced sympathetic activation that may prevent left ventricle overload in hypertensive PMW.

Effects of chronic dietary grape seed extract supplementation on aortic stiffness and hemodynamic responses in obese/overweight males during submaximal exercise.

We investigated the effect of chronic grape seed extract (GSE) on blood pressure and aortic stiffness (AoS) among overweight and obese males. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (Q), total vascular conductance (TVC), and AoS were measured during two submaximal cycling exercises (40% and 60% VO2max), after 7 consecutive days of GSE or placebo (PL) ingestion with one week washout period. Compared with PL, GSE supplementation significantly decreased MAP at rest (85 ± 3 mmHg vs. 82 ± 3 mmHg), 40% (102 ± 3 mmHg vs. 99 ± 3 mmHg), and 60% workloads (109 ± 3 mmHg vs. 107 ± 3 mmHg) (P = 0.001, ES = 0.2). AoS was significantly reduced (13.0 ± 1.9 AU vs. 10.2 ± 1.0 AU) at rest (P = 0.002, ES = 0.6). Q was decreased at rest and across all workloads, but there were no significant differences (7.5 ± 0.4 L/min vs. 7.1 ± 0.4 L/min; 20.4 ± 1.2 L/min vs. 19.6 ± 0.9 L/min; 26.3 ± 1.1 L/min vs. 25.5 ± 1.6 L/min, respectively). GSE had no effect on HR, TVC, and SV. Our study indicates that chronic supplementation with GSE reduces arterial pressure at rest and during exercise primarily via the substantial reduction in AoS. Thus, GSE can be a dietary supplement to treat augmented blood pressure responses in obese and overweight males at rest and during exercise.Trial registration: ClinicalTrials.gov identifier: NCT04465110.

Combined L-Citrulline Supplementation and Slow Velocity Low-Intensity Resistance Training Improves Leg Endothelial Function, Lean Mass, and Strength in Hypertensive Postmenopausal Women.

Hypertension is highly prevalent in postmenopausal women. Endothelial dysfunction is associated with hypertension and the age-related decreases in muscle mass and strength. L-citrulline supplementation (CIT) and slow velocity low-intensity resistance training (SVLIRT) have improved vascular function, but their effect on muscle mass is unclear. We investigated whether combined CIT and SVLIRT (CIT + SVLIRT) would have additional benefits on leg endothelial function (superficial femoral artery flow-mediated dilation (sfemFMD)), lean mass (LM), and strength in hypertensive postmenopausal women. Participants were randomized to CIT (10 g/day, n = 13) or placebo (PL, n = 11) alone for 4 weeks and CIT + SVLIRT or PL + SVLIRT for another 4 weeks. sfemFMD, leg LM and muscle strength were measured at 0, 4, and 8 weeks. CIT increased sfemFMD after 4 weeks (CIT: Δ1.8 ± 0.3% vs. PL: Δ−0.2 ± 0.5%, p < 0.05) and 8 weeks (CIT + SVLIRT: Δ2.7 ± 0.5% vs. PL + SVLIRT: Δ−0.02 ± 0.5, p = 0.003). Leg LM improved after CIT + SVLIRT compared to PL + SVLIRT (Δ0.49 ± 0.15 kg vs. Δ0.07 ± 0.12 kg, p < 0.05). Leg curl strength increased greater with CIT + SVLIRT compared to PL + SVLIRT (Δ6.9 ± 0.9 kg vs. Δ4.0 ± 1.0 kg, p < 0.05). CIT supplementation alone improved leg endothelial function and when combined with SVLIRT has additive benefits on leg LM and curl strength in hypertensive postmenopausal women.

Effects of Acute Grape Seed Extract Supplementation on Hemodynamics in Normal Body Weight and Obese Males.

Recently, it has been reported that dietary supplementation with grape seed extract (GSE) ameliorates endothelial function and increase nitric oxide (NO) bioavailability. Thus, we investigated if elevated blood pressure and aortic stiffness (AoS) characterized in obese individuals are attenuated following acute GSE supplementation. Twenty men (obese=10; normal body weight (NBW)=10) participated in this study. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), and AoS were compared 2 h after ingestion of GSE or placebo (PL) on different days, 1 wk apart. Compared with the PL, GSE supplementation significantly decreased SBP (NBW: 103±4 vs. 99±3 mmHg; obese: 118±3 vs. 112±5 mmHg) and MAP (NBW: 75±2 vs. 72±2 mmHg; obese: 86±3 vs. 84±3 mmHg) in both groups, while there were no differences in HR, SV, DBP, TPR, and AoS. GSE supplementation significantly decreased CO in only obese group. In NBW group, TPR tended to be decreased, but there was no significant difference. Our study suggests that acute supplementation with GSE reduced both SBP and MAP via a reduction in CO in obese individuals and decreased peripheral vasoconstriction in NBW group.

Antimüllerian hormone and antral follicle count are lower in female cancer survivors and healthy women taking hormonal contraception.

OBJECTIVE: To determine the impact of hormonal contraception (HC) on markers of ovarian reserve, including antimüllerian hormone (AMH) and antral follicle count (AFC). DESIGN: Longitudinal prospective cohort. SETTING: University hospital. PATIENT(S): Young adult female cancer survivors and healthy similar-age women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Participants were followed annually to determine hormone levels and for transvaginal ultrasound. Subjects who used HC within the preceding 3 months were considered to be exposed. Linear mixed effects models were used to incorporate repeated measures and adjust for potential confounders. RESULT(S): A total of 249 women (126 survivors, 123 control subjects; average age 25.5 years) were followed for an average of 2.1 visits and 2.15 years. After adjusting for confounders, AMH was found to be 21% lower among survivors using HC and 55% lower among control subjects using HC (relative risk [RR] 0.79, 95% confidence interval [CI] 0.68-0.93; and RR 0.45, 95% CI 0.30-0.68; respectively). AFC was 20% lower among survivors and control subjects using HC (RR 0.80, 95% CI 0.69-0.93). When considering an individual subject, AMH was 17%-35% lower when a subject had recently used HC than when she had not (survivors: RR 0.83, 95% CI 0.75-0.93; control subjects: RR 0.65, 95% CI 0.55-0.78), and AFC was 11% lower (RR 0.89, 95% CI 0.82-0.96). Additive HC exposure across multiple visits was not associated with differences in AMH or AFC. CONCLUSION(S): AMH and AFC are significantly lower among women with recent exposure to HC. AMH and AFC should be interpreted with caution when measured in the setting of recent hormone use.

Quality of life in female cancer survivors: is it related to ovarian reserve?

PURPOSE: The purpose of the study is to assess the quality-of-life scores and possible association with measures of ovarian reserve in female cancer survivors compared to healthy controls of similar age. METHODS: In this prospective cohort study, fifty-nine cancer survivors aged 16-39 years and 66 healthy, similarly aged unexposed women were recruited at the University of Pennsylvania. The primary outcome measures are the generic and cancer-specific domain scores on the Quality of Life in Adult Cancer Survivors (QLACS) instrument, early follicular phase serum hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), inhibin B (INH), anti-Mullerian hormone (AMH), and ovarian ultrasound measurements [ovarian volume and antral follicle count (AFC)]. RESULTS: Cancer survivors had significantly higher total and cancer-specific domain scores compared to unexposed participants. Serum AMH, INH, ovarian volume, and AFC were lower while serum FSH was higher in cancer survivors. Although survivors exhibited diminished ovarian reserve, these markers were not independently associated with total QLACS score. Cancer survivors with irregular menstrual function were found to have lower quality-of-life (QOL) scores than those with regular cycles. CONCLUSIONS: We found that QOL appears to be significantly impaired in cancer survivors compared to controls, even when remote from initial cancer diagnosis. In addition, our study suggests that reproductive aging contributes to QOL in the setting of irregular menses and likely profound impairment of ovarian function.

What is normal ovarian reserve?

While hormonal and ultrasonographic measures of ovarian reserve are often used to counsel patients about their fertility potential, normative data for these markers in the general population are lacking. Most studies are cross sectional and take place within specific subpopulations. Antral follicle count and anti-Mullerian hormone have been shown to be the best indicators of a woman's total follicular reserve. Ovarian volume, inhibin B, estradiol, and follicle-stimulating hormone are less helpful. Antral follicle count and anti-Mullerian hormone decrease with age and have been used to attempt to predict the length of the fertile window. Additional longitudinal data are needed for these biomarkers in populations of young, healthy, multiethnic women to assess for the presence of cofactors and determine the rate of age-related decline. Currently, these biomarkers are insufficient as predictors of fertility potential or advancement to menopause and no definitive determinations can be made about what constitutes "normal" levels of each measure.

Pregnancy after cancer: results from a prospective cohort study of cancer survivors.

BACKGROUND: Future fertility is an important concern for many cancer survivors. Cancer therapies have been shown to adversely impact reproductive function. However, it is difficult to predict the extent to which reproductive dysfunction will occur. The purpose of this study was to compare measures of ovarian reserve (MOR) and pregnancy rates in young female cancer survivors and similar-aged controls. PROCEDURES: A prospective cohort study was conducted in a university-hospital setting. Participants were followed annually for a mean 25 months to assess reproductive history, the incidence of pregnancy, and MOR (serum follicle-stimulating hormone, luteinizing hormone, estradiol, inhibin B, anti-mullerian hormone (AMH), antral follicle counts and mean ovarian volume). RESULTS: Eighty-four female survivors (average age 26, and 14 years post-treatment) and 98 similar-aged controls that were sexually active with men were included. At baseline, 27/84 survivors and 42/98 controls reported a prior pregnancy. Adjusted models showed that anti-mullerian hormone (AMH) and antral follicle count (AFC) were impaired in survivors with a prior pregnancy compared to controls with a prior pregnancy (P < 0.01, P = 0.03). During follow-up in 56 survivors and 74 controls, 19 pregnancies occurred in survivors and 18 in controls. Comparison of MOR between survivors who became pregnant and controls who became pregnant revealed that AMH and AFC were impaired in survivors (P < 0.05). Compared to survivors who did not become pregnant, survivors who did were older (P < 0.01) and more likely to be cohabitating (P < 0.01), but had similar MOR and exposure to alkylators (P = 0.34). CONCLUSIONS: Survivors achieved pregnancy at a rate similar to controls despite impaired MOR.

Response to ovarian stimulation in patients facing gonadotoxic therapy.

Chemotherapy naïve patients undergoing embryo/oocyte banking for fertility preservation (FP) were assessed for response to ovarian stimulation. Fifty FP patients facing gonadotoxic therapy were matched by age, race, cycle number, date of stimulation and fertilization method to patients undergoing IVF for infertility or oocyte donation. There were no differences in baseline FSH, anti-Müllerian hormone, antral follicle count and total gonadotrophin dose. FP patients had more immature oocytes (2.2 versus 1.1; P=0.03) and lower fertilization rates per oocyte retrieved (52% versus 70%; P=0.002). There were no differences in numbers of oocytes retrieved, mature oocytes or fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses (3077IU versus 2259IU; P=0.0477) and had more immature oocytes (3.4 versus 1.2; P=0.03) than matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. Overall, chemotherapy naïve FP patients had similar ovarian reserve, response to stimulation and oocyte and embryo yield compared to controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole. With improvement in cancer survival rates, there has been a shift in attention toward management of long-term consequences of cancer therapy, including infertility. Many young women with cancer, particularly those who will be treated with chemotherapy, pursue fertility preservation (FP) strategies for the purpose of banking oocytes or embryos for future use. We examined patients with no prior exposure to chemotherapy who underwent IVF to freeze embryos or oocytes for FP. Fifty FP patients were identified and matched to healthy controls by age, race, cycle number, date of stimulation and fertilization method. There were no differences in baseline measures of ovarian reserve or amount of medication needed to stimulate the ovaries. FP patients had more immature oocytes and lower fertilization rates than controls. There were no differences in number of oocytes retrieved, number of mature oocytes, rate of maturity or number of fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses and had more immature oocytes compared with matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. We demonstrated that FP patients not previously exposed to chemotherapy have similar ovarian reserve, response to stimulation and oocyte and embryo yield compared with infertile and donor controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole.

Pretreatment antimüllerian hormone levels determine rate of posttherapy ovarian reserve recovery: acute changes in ovarian reserve during and after chemotherapy.

OBJECTIVE: To identify factors associated with ovarian reserve impairment during and immediately after chemotherapy. DESIGN: Prospective cohort study. SETTING: Four university hospitals. PATIENT(S): Forty-six adolescent and young adult women with a new diagnosis of cancer requiring chemotherapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Measurements of ovarian reserve via levels of serum follicle-stimulating hormone, luteinizing hormone, estradiol, inhibin B, and antimüllerian hormone (AMH) as well as antral follicle counts and mean ovarian volume at 3-month intervals. RESULT(S): Changes in ovarian reserve were quantified for both the acute impact of treatment using linear regression and the longitudinal recovery after therapy using mixed-effects models adjusted for baseline ovarian reserve, use of alkylating agent, and hormone use. The women had at least one pretreatment and two posttreatment study visits (mean follow-up interval: 12 months). All measures of ovarian reserve demonstrated statistically significant changes during chemotherapy. Alkylating agent exposure and baseline ovarian reserve were acutely associated with the magnitude of impairment, and pretreatment AMH levels were associated with the rate of recovery of AMH after treatment. In adjusted models, participants with a pretreatment AMH level > 2 ng/mL recovered at a rate of 11.9% per month after chemotherapy, whereas participants with pretreatment AMH levels ≤ 2 ng/mL recovered at a rate of 2.6% per month after therapy. CONCLUSION(S): Baseline ovarian reserve and alkylating agent exposure effect the magnitude of acute changes in ovarian reserve from chemotherapy. The rate of recovery of AMH is impacted by pretreatment levels. This should be considered during pretreatment fertility preservation counseling.

Sperm and oocyte cryopreservation: comprehensive consent and the protection of patient autonomy.

Sperm cryopreservation and increasingly oocyte cryopreservation are common forms of fertility preservation for oncology patients facing gonadotoxic therapy. Both procedures present challenging ethical issues with regard to informed consent, given that the context for these procedures is a disease that carries a significant risk of mortality. We argue that the current consent process does not allow for adequate collection of information about a patient's wishes for the custody of cryopreserved gametes in the case of premature death. After review of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine guidelines we propose that a new, comprehensive consent procedure for sperm and oocyte cryopreservation including a 'roll-down' option is imperative to protect the autonomy of these oncology patients. This 'roll-down' option should allow for the transfer of custody of gametes to a pre-selected alternative recipient(s) if the original recipient no longer intends to use the gametes to create a child. We also demonstrate that objections over non-spousal custody of gametes can be overcome with sound ethical arguments.

How and when human chorionic gonadotropin curves in women with an ectopic pregnancy mimic other outcomes: differences by race and ethnicity.

OBJECTIVE: To investigate the hCG profiles in a diverse patient group with ectopic pregnancy (EP) and to understand when they may mimic the curves of an intrauterine pregnancy (IUP) or spontaneous abortion (SAB). DESIGN: Retrospective cohort study. SETTING: Three university hospitals. PATIENT(S): One hundred seventy-nine women with symptomatic pregnancy of unknown location. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Slope of log hCG; days and visits to final diagnosis. RESULT(S): Of women with an EP, 60% initially exhibited an increase in hCG values, with a median slope of 32% increase in 2 days; 40% of subjects initially had an hCG decrease, with the median slope calculated as a 15% decline in 2 days. In total, the hCG curves in 27% of women diagnosed with EP resembled that of a growing IUP or SAB. Of the EP hCG curves, 16% demonstrated a change in the direction of the slope of the curve. This was more common in African Americans and less evident in Hispanics. Furthermore, it was associated with more clinical visits and days until final diagnosis. CONCLUSION(S): The rate of change in serial hCG values can be used to distinguish EP from an IUP or SAB in only 73% of cases. The number of women who had a change in direction of serial hCG values was associated with race and ethnicity.