[Problems of today in the field of endocrinology of reproduction].
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Biomedical subjects
Publications and source records attributed to B Lunenfeld.
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Prolonged exposure of cells to the potent protein synthesis inhibitor cycloheximide terminates in cell death. In the present study we investigated the effect of insulinlike growth factor-1, insulin, and epidermal growth factor on cell death induced by cycloheximide in the confluent MCF-7 cells, and correlated this effect to the inhibition rate of protein synthesis. Cell death was evaluated by measuring either dead cells by the trypan blue dye exclusion test or by the release of lactic dehydrogenase into the culture medium. After 48 h incubation, cycloheximide (10 to 50 micrograms/ml) was shown to induce cell death in a concentration-dependent manner. Insulinlike growth factor-1, at physiologic concentrations (0.2 to 5 ng/ml), reduced this cell death. Insulin at supraphysiologic concentrations (1 to 10 micrograms/ml) mimicked the effect of insulinlike growth factor-1, whereas epidermal growth factor (10 to 50 ng/ml) had no effect. More than 90% of protein synthesis measured by [3H]leucine incorporation was inhibited by 10 to 50 micrograms/ml cycloheximide. Insulinlike growth factor-1 and insulin at the concentrations that reduced cell death to control level, had no effect on the protein synthesis inhibition rate induced by cycloheximide. These results indicate that inhibition of cell death by insulinlike growth factor-1 does not depend on protein synthesis and may be mediated via a posttranslational modification effect.
Total progesterone receptor levels (TRP) were measured in various tissues and segments of normal human uteri in basal conditions (late proliferative phase, control group, n = 6) and after short term estrogen administration (test group, n = 8). Similar trends of distribution were observed in both groups in basal endometrial TRP levels along the longitudinal axis, i.e. the highest levels were found at the height of the body and the lowest at the height of the internal os. Differences were found in the trends of distribution of the TRP levels between the two groups along the transverse axis of the uterus at the height of the fundus. In the control group TRP levels in the functional endometrium were higher than those in the basal endometrium and myometrium. In the test group, however, the trend was reversed. Since the RP is estradiol induced and dependent, these results indicate the possibility of a selective estrogen effect on various segments or tissues in the human uterus.
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Accurate measurement of serum testosterone (T) is essential for proper diagnosis of androgen deficiency. There are now several modern assay technologies, including automated ones, for measurement of T. In this study, we compared analytical performance of five modern immunoassay technologies commonly used for measurement of total T: Vitros ECi (Ortho-Clinical Diagnostics; normal range (n.r.) 4.6-34 nmol/L); Architect (Abbott Laboratories; n.r. 9.7-34 nmol/L); Access (Beckman Coulter; n.r. 5.3-23 nmol/L); Delfia (Perkin-Elmer; n.r. 9.3-34 nmol/L); and manual EIA DRG kits (n.r. 8.3-42 nmol/L), with the classical RIA (3H-T), after extraction (n.r. 11-33 nmol/L), as a reference method. Total T was measured using all above-mentioned methods in serum samples from 100 male patients, aged 16-65 years. Mean T concentrations in these 100 serum samples assayed by all non-isotopic methods were statistically significantly higher than those obtained by RIA. Delfia showed the highest T levels (19.3 nmol/L versus 12.1 nmol/L by RIA) with a positive bias 60-100%. Almost similar results were obtained using Architect, with a positive bias 40-70%. The closest correlation in results was found between Vitros ECi and RIA (12.7 nmol/L versus 12.1 nmol/L). In the studied samples, the median of differences ranged from minimal (-0.4 nmol/L for Vitros ECi) to maximal (-7.25 nmol/L for Delfia). For all non-isotopic methods, with the exception of Vitros ECi, differences in subjects with low T level (< 10 nmol/L) were statistically significantly larger than in the subjects with high T (T > 10 nmol/L). All other methods showed different degrees of dissimilarities with the RIA, especially in the range of low testosterone concentrations, which is of importance in the clinical assessment of women and pubertal boys.
In two patients exhibiting eunuchoid features in association with normal sized testes and complete spermatogenesis concommittant with only occasional Leydig cells between the tubuli, (proven by testicular biopsy) an attempt was made to elucidate the factors leading to this condition. Both patients responded with significant rise in both plasma FSH and LH after administration of synthetic GnRH indicating pituitary responsiveness. However, no rise in either FSH or LH could be observed after administration of clomiphene citrate during three weeks of treatment indicating hypothalamic unresponsiveness to chemical stimuli. Although plasma testosterone levels rose significantly after administration of Human Chorionic Gonadotropin, estradiol remained unchanged during three weeks of HCG administration. A hypothesis is discussed which defines this syndrome in these two cases as primary Leydig cells failure, expressed in the inability of these to transform testosterone into estrogens, thus depriving pituitary and hypothalamus from a proper steroidal milieu necessary to adequate functioning.
To obtain optimal results with gonadotrophic therapy (HMG/hCG) in infertile males, strict selection of patients is of paramount importance. The use of algorithmic schemes permits the exclusion of patients with primary testicular failure, genetic and non-endocrine causes of infertility. This paper describes a retrospective study on the results of gonadotrophic therapy in 25 severe oligozoospermic males, preselected according to the above scheme and in whom levels of FSH, LH and Testosterone before and during GnRH stimulation were assessed. This study indicates that low basal levels of FSH, concomitant with low or lack of FSH response to GnRH stimulation may be useful in selection of patients with a fair chance of success for gonadotrophic therapy.
Pituitary response to synthetic regular GnRH, to a potent analogue (D-TRp6) and to placebo were compared in ten azoospermic males. FSH and LH were measured prior to and at given intervals following administration of each substance. In addition, plasma levels of testosterone and prolactin were measured. There was no significant difference in the magnitude of FSH and LH release following injection of their the regular or the analogue form of GnRH. However, plasma gonadotrophins remained elevated for significantly longer time periods following the administration of the analogue GnRH. In those patients in whom LH levels remained elevated for at least 24 hours the observation of elevated testosterone levels permitted the inference of adequate biological activity of endogenously produced LH. Patients who did not respond to the regular GnRH were also non-responsive to D-TRp6 GnRH. A surprising finding ws elevated prolactin levels 4-6 hours following GnRH administration. Placebo had no influence on gonadotrophins, testosterone and prolactin.
16 patients, 4 months to five years following unilateral torsion of the testis were evaluated as to semen quality and hormonal status. In patients operated within 12 hours of the onset of pain 44% had normal semen quality while in those operated following more than 12 hours only 20% had normal semen analysis. FSH, LH and testosterone levels were normal in 14 of the 16 patients. One patient had a low testosterone level and slightly elevated FSH, another patient had slightly elevated levels of both FSH and LH.
Experiments with spermatozoa of prepubertal hamsters aged 35-48 days were performed in order to determine if the appearance of spermatozoa with fertilizing capacity in the cauda epididymis during puberty is related to changes in their morphology, motility and number. Epididymal spermatozoa of prepubertal animals were evaluated for number, motility and morphology and were injected into one uterine horn of a female, following induction of ovulation. A comparable number of sperm from mature animals (which served as control) was injected into the contralateral horn. Prior to 40 days fertilizing capacity was nil. It increased thereafter and reached control levels of 74% at 48 day age. Concomitantly there was an increase in the number of sperm per cauda epididymidis from less than 1 million to 55 million. Following removal of spermatozoa from the cauda the motility increased from 24% motile cells at the age of 39 days to 66% at the age of 48 days when most cells exhibited progressive motility. The percentage of cells having normal morphology increased from 18% at the age of 39 days to 50% at the age of 48 days. Developmental processes resulting in improvement of cell motility, morphology and number are correlated with attainment of fertilizing capacity. These processes seem to be gradual and occur between time of completion of spermatogenesis and time when capacity for fertilization is achieved.
A successful GnRH treatment for hypogonadotropic hypogonadism is described. A 40 year old infertile patient due to Kallmann's syndrome, associated with obesity and NIDDM, was treated with HCG (5,000 IU/week) for 8 years. In an attempt to induce spermatogenesis HMG (75 IU/daily) was added for 2 years. During the combined gonadotropin treatment semen analysis indicated an improvement from azoospermia to 2 x 10(6) sperm/ml. Since semen quality remained poor and obviously no pregnancy was achieved, the last regime was replaced by a pulsatile GnRH treatment (5 mcg/90 minutes). Following 6 months sperm count increased up to 15 x 10(6) associated with normal motility and morphology. Patient's wife conceived after the second intrauterine insemination and delivered a full term healthy baby.
In this randomized prospective study, we determined the conception rate following intra-uterine insemination with washed and prepared sperm, or with the first portion of a split ejaculate, in couples with longstanding male (n = 27, 70 treatment cycles) or cervical infertility (n = 14, 29 treatment cycles). Folliculogenesis and ovulation were induced by human menopausal gonadotropin and human chorionic gonadotropin. Significantly more couples conceived in the male infertility group following intra-uterine insemination with washed sperm, than after intra-uterine insemination with split ejaculate (9 vs. 2; P less than 0.05), while no difference in pregnancy rate (2 vs. 2) was found by the two intra-uterine insemination methods in the cervical infertility group.
The effect of clomiphene citrate (CC) and of its Zuclomiphene (ZuC) and Enclomiphene (EnC) isomers on the reproductive organs of immature male rats under different experimental conditions is reported. CC, ZuC, and EnC were administered daily to groups of either intact or castrated rats between the age of 21-44 d. This led to inhibition of weight increase of testis and accessory glands in the intact group. Spermatogenesis was arrested at the stage of primary spermatocyte following CC and ZuC treatment, and at the stage of young spermatids by EnC treatment. In the castrated group clomiphenes significantly stimulated weight increase of seminal vesicles (SV) compared with castrated control animals, but the former group were unable to achieve organ weight gain comparable to that in normal controls. Administration of human Chorionic Gonadotropin (hCG) together with CC or each of its isomers to intact animals, abolished the drug effect on spermatogenesis and on reproductive organ growth. Administration of CC, ZuC, and EnC together with testosterone to castrated animals, abolished the drug effect on growth inhibition of accessory glands. In intact treated rats LH and testosterone secretion were suppressed by all forms of clomiphenes. In the castrated group ZuC proved to be the most potent inhibitor of LH secretion. Therefore, it is inferred that ZuC and EnC have different potencies as far as their biological activity in the immature male rat is expressed.
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Israel represents a developed country as far as demand and consumption of health services are concerned. The analysis of the Israeli health system reveals a significant trend of expansion in the intensity and the utilization of health services as well as an accelerated development of sophisticated technology, while the percentage of Gross National Product used for health expenditure remained constant and even decreased. Competing needs, reflecting population growth, a rapid aging process, new areas of treatment, and changes in use of health services, illustrate the aggravating issue of setting priorities. The permanent dilemma of the health system is oscillation between opposite trends: enlargement of public eligibility and technological capabilities and economic reduction and budget limitations. Is there a possibility that the insufficiencies of the system are built into patterns of thinking of those in the system, into its structure, and into its organization of health services delivery? Does the formulation of health policy influence, in terms of the outcomes of the system, priorities and allocation of resources? Does the process of decisionmaking reflect in an appropriate manner the epidemiologic data? Under the objective constraints, decisionmaking and health policy formulation become critical determinants of the ability to cope more efficiently and effectively with growing and changing needs. The authors suggest an alternative strategy of health decisionmaking that is more instrumental in order to prevent setbacks and to open new horizons for the future.