Prospective randomized comparison of human chorionic gonadotropin versus intramuscular progesterone for luteal-phase support in assisted reproduction

Objective The purpose of the study was to determine the impact of two forms of luteal-phase supplementation, human chorionic gonadotropin (hCG) and progesterone (P), during gonadotropin releasing hormone agonist (GnRha)/controlled ovarian hyperstimulation (COH) cycles.Design and Patients The study was a prospective, randomized evaluation of 77 patients. Group 1 patients (n=38) received 2000 IU of hCG, injected subcutaneously, on days 3, 6, 9, and 12 after transvaginal aspiration of the oocytes (TVA=day 0). Group 2 patients (n=39) received 50-mg daily injections of intramuscular (i.m.) P from days 2 to 14 after TVA. Blood tests were performed on days 0, 5, 8, and 12 after TVA.Setting The in vitro fertilization program of a tertiary care institution was the study setting.Main Outcome Measures The main outcome measures were (1) pregnancy and implantation rates; (2) serum estradiol (E), P, and hCG levels; and (3) occurrence of side effects.Results Clinical pregnancy and implantation rates in group 1 versus group 2 were similar (36.7 vs 35.3 and 12 vs 14%, respectively). Regardless of pregnancy occurrence, on days 8 and 12 after TVA, serum E and P levels were higher in group 1 than group 2 but the resulting E/P ratios were similar. Five of 38 patients (group 1) developed moderate to severe ovarian hyperstimulation syndrome (OHSS) right after the first or second supplementary hCG injection. In these patients, the mean serum E level on the day of hCG trigger injection was about 3250 pg/ml and the number of follicles was between 9 and 17. In 6 of 39 patients (group 2) allergic reactions were observed at the P injection sites.Conclusions Based on our data, hCG administration as a form of luteal supplementation did not translate, in comparison to P, into significant benefits for the patients. At the same time, it significantly increased the risk of ovarian hyperstimulation. We suggest that whenever, during COH cycles, serum E levels are over 2500 pg/ml and the number of follicles exceeds 10, luteal support with hCG should be excluded.Presented at the 41st Annual Meeting of the Pacific Coast Fertility Society, Indian Wells, California, April 14–18, 1993.     

Tamoxifen Paradoxically Decreases Paclitaxel Deposition into Cerebrospinal Fluid of Brain Tumor Patients

Summary Background: P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood–cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF). Methods: Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m²/IV) or a course of TAM (160 mg/m² PO BID on Days 1–5) followed by paclitaxel (175 mg/m²/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays. Results: Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel–TAM groups ranged between 3.5–57.4 and 2.3–24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel–TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone. Conclusions: The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp’s localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.     

Survey on the use of complementary and alternative medicine among patients with headache syndromes

The objective was to determine headache patients' knowledge, prevalence of use and perceived effectiveness of complementary and alternative medicine. Seventy-three patients with headache syndromes attending a head and neck pain clinic were interviewed using a standardized questionnaire. Alternative medical therapies were used by 85% of surveyed patients for the relief of their head pain. In 60%, the therapies were perceived to have a benefit. Almost 100% of the patients were familiar with one or more of the presented alternative treatments. Eighty-eight per cent perceived at least one of the complementary treatments to be an effective remedy for headache pain. Exposure to and interest in alternative treatments are common among patients with headache syndromes, despite the lack of scientific evidence of benefit and assessments of risks for many of the treatments. Neurologists and general physicians should be aware of the increasing role of alternative medicine in the healthcare system. There is still an urgent need for objective, integrative and critical research with regard to complementary and alternative medicine.     

Infertility: Is there a role for ovarian stimulation and intra-uterine insemination after age 40?

The objective of this study was to determine the conceptionrate in infertile couples in which the female partner was40years old and who had received ovarian stimulation treatmentand intra-uterine insemination (IUI). It was a retrospectivestudy of 77 patients who underwent a total of 210 treatmentcycles. Protocols for ovulation induction included clomiphenecitrate, human menopausal gonadotrophin (HMG) and clomiphenecitrate plus HMG. Patients were monitored using transvaginalultrasound, and two IUI were performed 24 and 48 h after thedetermination of urinary luteinizing hormone (LH) surge or humanchorionic gonadotrophin (HCG) injection. A total of 11 pregnancieswere reported, giving a pregnancy rate of 14% per patient and5% per cycle. Eight spontaneous abortions occurred, giving apregnancy wastage of 73%. In a previous comparative analysisof 543 patients <39 years old receiving IUI and identicalprotocols of ovarian stimulation, 141 pregnancies were achieved,giving a pregnancy rate of 21% per patient and 10% per cycle.The miscarriage rate in that group was 18%. This report comparesIUI results for women 40 years with those obtained previouslyfor younger women, and shows the very poor success rate in women>40 years of age. This information will be important in theproper counselling of this group of patients, as well as indicatingthat a prompt recommendation for assisted reproductive treatmentshould be made soon after the failure of a few attempted cyclesof ovarian stimulation treatment and IUI.     

Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups.

In a retrospective analysis of 637 cycles of ovarian stimulation and transvaginal follicular aspiration for various assisted reproductive technologies, severe ovarian hyperstimulation syndrome (SOH) occurred in six (0.94%) cycles. The patients at a high risk of developing SOH in cycles of assisted reproduction were those who had excessive serum oestradiol levels on the day of human chorionic gonadotrophin (HCG) administration (oestradiol greater than 6000 pg/ml; 38% SOH) and a high number of oocytes obtained (greater than 30 oocytes; 23% SOH). In those patients with both oestradiol greater than 6000 pg/ml on the day of HCG administration and greater than 30 eggs retrieved, the chance of developing SOH was 80%. The higher the serum oestradiol levels and the more eggs retrieved, the higher the pregnancy rates observed. High oestradiol level did not appear to have a detrimental effect on pregnancy rates and outcome. Furthermore, our results are not consistent with suggestions that the addition of gonadotrophin-releasing hormone agonist to ovarian stimulation protocols, follicular aspiration and/or luteal support with progesterone may reduce the incidence of ovarian hyperstimulation syndrome.     

Tubal embryo transfer in cynomologus monkeys: effects of hyperstimulation and synchrony

To date the main limitation of in-vitro fertilization–embryotransfer (IVF–ET) programmes is that transcervical transferof embryos results in a rate of low implantation. On the otherhand, the technique of gamete intra-Fallopian transfer (GIFT)does not contribute to information on oocyte fertilization rates,and the time of oocyte exposure to sperm may be limited. Thedevelopment of ultrasonically guided follicular aspiration willallow transfer of embryos generated in vitro to the Fallopiantubes performing only one surgical procedure in the process.We have perfonnd 25 intra-tubal embryo transfers in the cynomolgusmonkey (Macaca fascicularis). Ovarian stimulation, folliularaspiration and IVF procedures have been reported previouslyby Balmaceda. ETs were performed via laparotomy. Embryos atthe 2-, 4- or 9-cell stage were loaded into a tom-cat catheterin 5 ?l of culture medium and delivered to the mid-ampullaryportion of the tube. Seven ETs performed during stimulated cyclesresulted in one pregnancy, and 18 ETs performed in synchronizedrecipients resulted in six pregnancies. Ten ETs were performed0–24 h, eight performed 24–48 h and seven performed72–110 h after follicular aspiration or ovulation, andresulted in 4, 3 and 0 pregnancies respectively. Our resultsdemonstrate that intra-tubal embryo transfer can result in normalintra-uterine pregnancies and suggest that both ovarian stimulationand cycle synchronization affect the probability of embryo implantation.     

Congenital absence of the vas deferens. The fertilizing capacity of human epididymal sperm

BACKGROUND. Congenital absence of the vas deferens has been considered a virtually untreatable cause of male sterility. Furthermore, sperm that have not passed through at least the head of the epididymis have been thought to be incapable of causing pregnancy. We attempted to determine whether human sperm that had never passed through the epididymis could fertilize eggs in vitro and whether the technique could be used for men with congenital absence of the vas deferens. METHODS. Twenty-eight men with congenital absence of the vas deferens underwent microsurgical aspiration of sperm from the epididymis and vasa efferentia for attempted in vitro fertilization of their wives' oocytes, with subsequent transfer of embryos. Thirty-two treatment cycles were begun (four were repeat cycles). RESULTS. The most motile sperm were found in the proximal epididymis, at or near the vasa efferentia. Embryos were obtained for transfer in 21 cases (66 percent). Ninety-three embryos resulted from 352 mature oocytes (fertilization rate, 26 percent). Clinical pregnancy was achieved in 10 of the 32 treatment cycles (31 percent). Seven women delivered normal infants, and three miscarried. One of the seven live births was of twins. There were six girls and two boys. When fewer than 10 eggs were retrieved, no pregnancy occurred. When 10 or more eggs were retrieved (20 cases), the pregnancy rate was 50 percent. CONCLUSIONS. Sperm from the proximal caput epididymidis and even sperm from the vasa efferentia (which have never passed through the epididymis) can fertilize the human oocyte in vitro and result in pregnancy with live birth.     

Programming of ovarian stimulation with norethindrone acetate in IVF/GIFT cycles

Twenty patients were given norethindrone acetate (NET) to program the initiation of controlled ovarian hyperstimulation and to coordinate follicular aspiration with surgery to obtain spermatozoa from the husband. Patients received NET, 10 mg/day orally, starting between days 2 and 4 of the cycle. The duration of NET therapy varied from 9 to 37 days. The mean time of onset of vaginal bleeding, after cessation of NET, was 2.9 +/- 0.7 days. Ovarian stimulation was carried out with a combination of a luteinizing hormone releasing hormone analog, follicle-stimulating hormone and human menopausal gonadotrophin. The day of human chorionic gonadotrophin (HCG) administration ranged from day 8 to day 15 of the cycle (10.1 +/- 1.7). On the day of HCG injection, the mean E2 level was 2188 +/- 1126. The mean number of follicles aspirated was 18.4 +/- 9.9 per cycle. The mean number of oocytes collected per cycle was 15.5 +/- 8.5. There was no correlation between duration of NET suppression and the number of days of gonadotrophin therapy needed to reach HCG administration. The large number of oocytes retrieved is probably related more with the fact that the patients represented a group with a purely male factor of infertility, than by the specific drug protocol utilized. Our results demonstrate that the ovarian response to gonadotrophin stimulation was not affected by NET administration. The main advantages of the use of this drug for cycle control are that its administration is oral, simple and inexpensive.     

Handgrip Strength: Associations with Clinical Variables,Body Composition,and Bone Mineral Density in Adults with Cystic Fibrosis

Background: Loss of fat-free mass (FFM) is associated with an increase in morbidity and mortality in cystic fibrosis (CF) patients. Handgrip strength (HGS) measures muscle function and may be associated with clinical parameters with prognostic value. Our objectives were to evaluate muscle strength through HGS in CF patients and to determine if there are any associations with respiratory clinical variables, FFM, and bone mineral density (BMD). Methods: A cross-sectional study conducted in clinically stable patients. We evaluated muscle function through HGS, respiratory function—forced expiratory volume in 1 s (FEV1) (%), forced vital capacity (FVC) (%), bronchorrhea, annual exacerbations, and body composition (FFM and FFM index, FFMI: fat-free mass in kg/height in m²) and Bone Mineral Density (BMD) through densitometry (DXA). Results: The study included 53 CF patients (58.5% females, mean age 28.3 ± 8.1, body mass index (BMI) 21.7 ± 3.4). The mean values for dynamometry were 40.2 ± 8.1 kg in males and 23.1 ± 7.0 kg in women, being 20.8% below the 10th percentile. Patients with lower muscle strength showed significantly more exacerbations and lower FEV1% and FVC%, as well as lower BMI, worse BMD (g/cm²), T-score, and Z-score. A significant and positive correlation was found between the mean and maximum dynamometry values and age, FVC%, BMI, FFMI, FFM (kg), and BMD. Conclusions: For adults with CF, HGS is a practical tool for assessment of health status. Low values reflect poor nutritional status and are associated with poor respiratory function, low fat-free mass and low bone mineral density.     

Non-surgical tubal embryo transfer

Selective cannulation of the Fallopian tubes via the utero-tubal junction, without analgesia, anaesthesia or surgery, has been carried out to replace three embryos in a patient. Cannulating the Fallopian tubes did not appear materially to affect the transport of embryos or the receptivity of the endometrium for implantation.