Biomedical subjects
Publications and source records attributed to Z Shoham.
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The objective of the present study was to evaluate the pharmacokinetics of human chorionic gonadotropin (hCG) following different regimens of subcutaneous and intramuscular single-dose administration. Two hypogonadotropic hypogonadal volunteers received hCG injections without prior ovarian stimulation. The regimens included a single dose of 10,000 IU hCG either subcutaneously or intramuscularly, or 5000 IU hCG intramuscularly. Serum beta-hCG concentrations were measured periodically up to 13 days after hCG administration. Each of the three regimens exhibit a similar pharmacokinetic profile and the highest serum beta-hCG concentrations were achieved with a dose of 10,000 IU administered subcutaneously. Seven days after hCG administration beta-hCG was detectable only after subcutaneous or intramuscular administration of 10,000 IU, but not after a single intramuscular injection of 5000 IU. From the preliminary results of the study it is suggested that a single intramuscular dose of 5000 IU hCG might be sufficient to trigger ovulation, but for luteal-phase support a higher dose may be needed. Subcutaneous administration of hCG for the induction of ovulation or luteal-phase support in gonadotropin-induced cycles is feasible and might offer a better tolerance and cost-effectiveness of infertility treatments, leading to their further simplification.
The objective of this study was to induce spermatogenesis by co-treatment with growth hormone and gonadotropins in normogonadotropic patients with severe oligoteratoasthenospermia (OTA) who had failed to respond adequately to conventional therapy. A prospective study in which co-treatment with growth hormone (4 IU) and human menopausal gonadotropin (hMG; 150 IU of follicle-stimulating hormone (FSH) and 150 IU of luteinizing hormone (LH)), three times a week, and human chorionic gonadotropin (hCG; 2500 IU), two times a week for 24 weeks, were administered after unsuccessful treatment for at least 12 weeks with gonadotropins. Four patients who had failed to respond to conventional treatment with gonadotropins participated in the study. Semen volume, sperm production, serum testosterone, LH, FSH, insulin-like growth factor-I (IGF-I) and growth hormone-binding protein concentrations were used to measure outcome. In all four patients, there was no improvement in sperm quality as compared to baseline measurements. Serum testosterone concentrations remained within normal limits. A significant increase in both serum IGF-I and growth hormone-binding protein was found following treatment with growth hormone. Our results do not encourage the use of co-treatment of gonadotropins with growth hormone in cases of normogonadotropic OTA syndrome patients who fail to respond adequately to the conventional therapy with gonadotropins.
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OBJECTIVE: To compile updated information regarding gonadotropin secretion, specifically the physiology of the midcycle LH surge, in natural cycles and under various ovulation induction protocols. DATA IDENTIFICATION AND SELECTION: Studies that deal with the clinical aspects of LH surge manipulation or substitution were identified through literature and Medline searches. RESULTS: Three major regulatory factors have been identified as participants in the induction of the midcycle gonadotropin surge. These are hypothalamic GnRH secretion, ovarian and adrenal steroids, and less well-characterized ovarian peptide hormones. Gonadotropin-releasing hormone pulsatility is regulated by a complex mechanism that integrates multiple neurotransmitters and sex steroids. Estradiol plays a central role in the pituitary secretion of LH, which also is influenced by P concentrations. Gonadotropin surge attenuating factor also has been implicated in the regulation of timing and amplitude of the LH surge. Human chorionic gonadotropin is used extensively as a LH surrogate, but its use is associated with a number of disadvantages. Induction of an endogenous LH surge through use of the flare effect of GnRH analogues has been examined more recently and has been found to have several advantages. Recombinant human LH is in the final stages of clinical testing. CONCLUSION: Although much is known about the physiology of the midcycle LH surge and its variations under different clinical conditions, new approaches to the induction or substitution of the LH surge currently are being examined and learned. The introduction of recombinant gonadotropins into clinical practice is likely to influence ovulation induction and IVF practice to a significant degree in the near future.
Our objective was to compare recordings of flow velocity waveforms from the uterine artery via the transvaginal and transabdominal approach in normal human pregnancies. In a cross-sectional study from 16 to 40 weeks' gestation, 88 healthy pregnant women underwent a continuous-wave Doppler examination of their uterine arteries by both the transvaginal and the transabdominal approach. Measurements were recorded for both uterine arteries and averaged. Values recorded transabdominally were significantly lower than those obtained transvaginally in all patients < or = 27 weeks' gestation. From 28 weeks to term, transabdominal values remained lower, but the difference was smaller and insignificant, and noted only as a trend. Transvaginal velocimetry of the uterine artery produces significantly higher systolic:diastolic ratios than that of transabdominal recordings until 27 weeks' gestation. Thereafter, trophoblastic invasion of the uteroplacental circulation is maximal, and the difference between the values are minimal and insignificant. However, a pattern of lower resistance in the transabdominal approach remains consistent until term.
A 29-year-old nullipara with partial hydatidiform mole at 8 weeks had pre-evacuation hCG levels of 275,000 mIU/ml. Free beta-hCG levels were measured as 3% (normal value below 4%). The patient developed persistent gestational trophoblastic disease, failed to respond to methotrexate and actinomycin D, but has responded to combination chemotherapy with EMA-CO. Such a response to EMA-CO was not reported previously.
OBJECTIVE: To collate information relating specifically to amenorrhea of different etiologies in young women, the long- and short-term implications of these states, and the optimal therapeutic strategy to treat these conditions. DATA IDENTIFICATION: Studies related to these topics were identified through literature and Medline searches. STUDY SELECTION: Those studies that relate specifically to amenorrhea in women of reproductive age, including etiology, diagnosis, and the implications of replacement therapy or nontreatment of this state, were selected. RESULTS: Amenorrhea, as defined by the absence of menses for > or = 6 months, may be found in up to 3% of women in the reproductive years. Classification of amenorrhea involves defining the exact cause for the cessation of menses, be it hypothalamic, pituitary, ovarian, or lower genital tract in origin. The majority of amenorrheic young women have very low levels of estrogens, and a minority will have subnormal noncyclic estrogen levels, unopposed by P, due to anovulation. This distinction is important in considering the long-term implications of amenorrhea. Hypoestrogenic amenorrhea is associated with a significant loss of bone mineral density and the associated risk of osteoporosis and fractures. Lipoprotein profiles are also adversely affected, and this is associated with an increased risk of cardiovascular events. Anovulatory amenorrhea due to "unopposed" estrogen is associated with an increased risk of endometrial hyperplasia and endometrial carcinoma even in young patients. Therapy should be aimed at treating the underlying cause of amenorrhea, if possible, or reconstitution of an estrogen-P biphasic monthly cycle if not. CONCLUSIONS: Untreated amenorrhea is associated with significant long-term morbidity, especially in young women. Early recognition and institution of treatment will minimize late complications.
OBJECTIVE: To evaluate the efficacy of i.v. administration of human albumin solution for the prevention of severe ovarian hyperstimulation syndrome (OHSS). DESIGN: A prospective, randomized, placebo-controlled study comparing the effects of i.v. administration of human albumin solution versus sodium chloride 0.9% solution at the time of oocyte retrieval with patients undergoing IVF-ET who are at high risk for the development of severe OHSS. SETTING: Specialized assisted reproduction unit. PATIENTS: Thirty-one patients undergoing IVF-ET who had serum E2 levels of 1,906 pg/mL (> 7,000 pmol/L) and multiple follicular development on the day of hCG administration. INTERVENTIONS: After hCG administration, patients were randomized to receive i.v., either 50 g of human albumin diluted in 500 mL of sodium chloride 0.9% or 500 mL of sodium chloride 0.9% at the time of oocyte retrieval. MAIN OUTCOME MEASURES: Ovarian size as measured by pelvic ultrasonography, development of ascites, serum E2 concentrations during the luteal phase, and results of the IVF-ET cycles. RESULTS: Although no patient who had received human albumin solution developed severe OHSS, there were four such cases in the control group. All four were hospitalized with marked ascites and ovarian enlargement. There were no significant differences between the two groups comparing serum E2 levels on the day of hCG administration and during the luteal phase, the number of oocytes retrieved, fertilization, and pregnancy rates. CONCLUSIONS: Our preliminary results suggest that the administration of human albumin solution may help to prevent the development of severe OHSS in high-risk patients. Further research is needed to assess the potential of this novel approach.
OBJECTIVE: To review studies that have examined the epidemiology and etiology of the development of epithelial carcinoma of the ovary. DATA IDENTIFICATION: Important published studies related to the topic were identified through a computerized bibliography search. CONCLUSION: A review of the literature reveals that the etiology of epithelial ovarian cancer is probably multifactorial and that genetic, environmental, hormonal, and viral factors appear to be directly or indirectly related to the development of the disease. An attempt to implicate specific agents has not produced conclusive results. However, based on large epidemiologic studies, it seems that there is a clear trend of decreasing risk with increasing number of pregnancies, deliveries, use of oral contraceptives, and the duration of breast feeding. An increased risk was found to be associated with ovarian dysfunction leading to infertility and exposure to asbestos and talc. The recent observation that infertile women who used fertility drugs might experience an increased risk for the development of epithelial ovarian cancer should be examined very carefully because of the small number of patients in the study, lack of appropriate information about the type of infertility, drugs used, dosage, and duration of treatment. Because there are no screening tests that are consistently accurate enough to detect ovarian cancer at an early stage, translating the current information into disease prevention requires careful clinical evaluation with a routine follow-up of patients at risk.
This study was designed to examine ovarian performance, i.e. follicular growth, normal steroidogenesis and luteal phase function, following the administration of multiple increasing doses of human follicle stimulating hormone (FSH) with a constant low dose of luteinizing hormone (LH) in women with isolated hypogonadotrophic hypogonadism. Human menopausal gonadotrophin (HMG) was used in the first treatment cycle, starting with 150 IU of LH and 150 IU of FSH per day, for 7 days. The dose was increased daily with 75 IU of LH and 75 IU of FSH for another 7 days if no response was detected by serial ultrasound measurements and serum oestradiol determinations. In the second treatment cycle, a constant dose of 75 IU of LH (using HMG) was administered per day and up to 150 IU of FSH (using urofollitrophin) was supplemented. If no response was detected after 7 days of treatment, the dose of FSH was increased. For the final stage of ovulation induction, human chorionic gonadotrophin (HCG) was administered in the presence of at least one follicle > 17 mm in diameter but with no more than three follicles > 16 mm in diameter. To verify the adequacy of the luteal phase, a pharmacokinetic/pharmacodynamic study of beta-HCG, oestradiol and progesterone was performed following the second treatment cycle only. Ovarian stimulation using a constant dose of 75 IU of LH and increasing doses of FSH up to 225 IU, resulted in normal follicular growth and hormonal milieu. Both women showed normal luteal phase oestradiol and progesterone production and both women conceived following the second treatment cycle.
Seven women suffering from hypogonadism due to previous hypophysectomy, isolated gonadotrophin deficiency, or Kallman's syndrome [median age 39 years (range 24-45)] volunteered to participate in a study to assess ovarian response following multiple-dose administration of recombinant human follicle-stimulating hormone (rhFSH; Org 32489). Baseline serum FSH and luteinizing hormone (LH) concentrations were 0.25 (< 0.05-1.15) IU/l and 0.06 (< 0.05-0.37) IU/l, respectively. Subjects received daily i.m. injections of rhFSH for 3 weeks (week 1: 75 IU/day, week 2: 150 IU/day, week 3: 225 IU/day). Blood sampling and sonographic investigations were performed on alternate days. Steady-state FSH concentrations were reached approximately 3-5 days after alterations of the doses administered. Maximum FSH concentrations were between 7.1 and 11.8 IU/l, whereas serum LH concentrations remained unchanged. Due to absent follicle development and lack of a rise in immunoreactive inhibin (INH) (response failure possibly due to early ovarian failure or resistant ovary syndrome) in two subjects, analysis of ovarian response was restricted to five volunteers. Serum androstenedione levels showed no significant changes during rhFSH administration. Although serum immunoreactive INH concentrations reached normal late follicular values [659 (388-993) IU/l], serum oestradiol revealed only a minor increase [77 (18-210) pmol/l]. Moreover, growth of (multiple) ovarian follicles was observed up to pre-ovulatory sizes (> 15 mm) in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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The pathophysiological mechanism underlying polycystic ovarian disease (PCOD) is different in obese and lean women. In obese patients the basic disorder is insulin resistance and hyperinsulinemia. In non-obese women the dominant derangement is a relative excess of luteinizing hormone (LH) and growth hormone (GH) production. The levels of GH, LH, sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein-1 (IGFBP-1) were significantly lower and insulin levels considerably higher in obese PCOD women as compared to their non-obese counterparts. There was, however, no difference in the mean IGF-1 levels found in these two groups. The present study was designed to investigate whether, in addition to the mean levels, the overnight pattern of GH, IGF-1, IGFBP-1 and SHBG differed in obese women with polycystic ovaries as compared to that observed in the non-obese PCOD patients. Eight women with PCOD diagnosed by clinical, sonographic and hormonal means were studied. Four had basal body mass index exceeding 27. Blood samples were collected every 20 min over a period of 8 h, starting at 23:00 h. Twenty-four samples were collected from each patient and examined in one batch for GH, IGF-1, IGFBP-1, SHBG and insulin. The secretion patterns of the above substances during the late night (23:00-03:00 h) and early morning (03:00-07:00 h) hours were examined and compared in obese and non-obese PCOD women. Neither GH nor IGF-1 showed a distinct overnight secretion pattern. The overnight secretion patterns of IGFBP-1 and SHBG were similar in obese and non-obese women--the former showing a constant rising during the night and the latter exhibiting a converse trend. The integrated insulin levels were much higher during the late night as compared to early morning hours in all patients. It is proposed that the specific secretion pattern of IGFBP-1 is not directly dependent on body fat mass but is regulated by insulin in both obese and non-obese patients.
OBJECTIVE: To examine the safety, tolerance, pharmacokinetics, follicular growth, and steroidogenesis after the administration of recombinant human FSH (Org 32489; Organon International, Oss, The Netherlands) in women with isolated hypogonadotropic hypogonadism. DESIGN: An open phase I multiple rising dose study with recombinant FSH in two hypogonadotropic but otherwise healthy women. The drug was administered intramuscularly one time per day for a maximum of 21 days, i.e., 75 IU for the first 7 days, 150 IU for the next 7 days, and 225 IU during the last 7 days. Treatment was discontinued if serum E2 was > or = 1,100 pmol/L and/or one or more growing follicle > 14 mm in diameter was observed. After the last recombinant FSH injection, subjects were monitored for another 3 weeks. SETTING: Specialist Reproductive Endocrinology and Infertility Unit. VOLUNTEERS: Two women with isolated hypogonadotropic hypogonadism who did not want to get pregnant anymore. MAIN OUTCOME MEASURES: Serum FSH, androstenedione (A), T, P, LH, follicular growth, and endometrial thickness. Safety parameters: blood pressure, heart rate, urinalysis, hematology, blood biochemistry, and antirecombinant FSH antibodies. RESULTS: Treatment with recombinant FSH resulted in dose-related increases of serum FSH. Both women showed follicular growth (diameter, 17 mm), whereas serum A concentrations were very low, and serum E2 concentrations rose to only 76.7 and 139.5 pmol/L, respectively. No antirecombinant FSH antibody formation or changes of safety variables were noted. CONCLUSION: This study in two women with hypogonadotropic hypogonadism is consistent with the two-cell theory that FSH alone can induce follicular growth. The low concentrations of A and E2 indicate the need for LH to induce appropriate steroidogenesis. It was also found that recombinant FSH is well absorbed, safe, and well tolerated after daily treatment for up to 21 days.
OBJECTIVE: To review studies that have examined the role of LH, its mechanism of action, and its detrimental effects when hypersecreted during the follicular phase. DESIGN: Important published studies related to this topic were identified through a computerized bibliographic search. PATIENTS, PARTICIPANTS: Review of the need for LH during the follicular phase is based on animal models and women with hypogonadotropic hypogonadism. The association of hypersecretion of LH during the follicular phase with low rates of fertilization and high rates of pregnancy loss is based on clinical studies conducted in patients treated by IVF and ET and by induction of ovulation. The possible mechanism by which the effects occur is based on in vitro studies. RESULTS: The results of the studies cited in this review are consistent with the two-cell two-gonadotropin hypothesis implying that synergistic action of both FSH and LH is required for appropriate steroidogenesis. It also seems that, whatever the underlying mechanism, a raised serum LH concentration during the follicular phase confers a substantial risk of infertility and early pregnancy loss. CONCLUSION: By reviewing the literature it appears that LH exhibits an important role in the development of the growing follicle and maturation of the oocyte. It also seems that hypersecretion of LH during the follicular phase implies adverse effects on the fertility process. To further test this hypothesis, we now need systemic assessment of the methods of therapy used for treating patients with polycystic ovary syndrome, in relation to LH secretion and outcome of pregnancy.
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This study was designed to investigate the basic concentrations of different hormones in obese and non-obese patients with polycystic ovarian disease (PCOD). Eight women with PCOD, of whom four were obese with body mass index (BMI, kg/m2) of > 25 and four were non-obese with BMI < 25, volunteered to participate in this study. Serum samples were taken every 20 min over an 8 h period, starting at 2300 h, on day 5 of a spontaneous or gestagen-induced cycle. Basic insulin concentration was found to be significantly higher in the obese women compared with their non-obese counterparts (P < 0.0001). Serum concentrations of insulin-like growth factor binding protein (IGFBP-I) and sex hormone binding globulin (SHBG) were found to be significantly lower (P < 0.001 for both hormones) in the obese compared with the non-obese women. Serum concentrations of insulin-like growth factor I (IGF-I) did not differ between the two groups. The non-obese women had significantly higher serum concentrations of luteinizing hormone (LH) (P < 0.001) and of growth hormone (GH) (P < 0.002) than their obese counterparts. Based on these results, two models of the development of PCOD were suggested. In obese women, hyperinsulinaemia causes an excessive production of androgens through the enhancement of IGF-I receptors which, in synergism with LH, causes increased activity of cytochrome P-450c 17a. In non-obese patients, relative increase of GH concentration stimulates excessive ovarian IGF-I production. At this point synergism with LH results in excessive production of androgens by the same mechanism as in obese patients.(ABSTRACT TRUNCATED AT 250 WORDS)