Biomedical subjects
Publications and source records attributed to C B Coulam.
Four patients who had no oocytes retrieved during an IVF cycle were studied in an attempt to identify predictors of such an occurrence and suggestions for its cause. All 30 follicles aspirated in five cycles in these four women yielded no oocytes. One patient had two cycles that produced no eggs. The empty follicle syndrome may represent a new syndrome and a cause of infertility.
Until recently, the immunologic tolerance between a mother and her allogeneic fetus has been a highly speculative and poorly understood phenomenon. New data indicate that maternal acceptance of the fetal allograft necessitates a specific, protective immune response. This specific recognition apparently involves unique placental antigens with genes that are closely linked to HLA loci. Lack of recognition of these antigens, as in matings between partners with similar HLA profiles, may result in repeated spontaneous abortions caused by unsuppressed rejection mechanisms.
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Collagen-induced arthritis (CIA) in mice is a model of inflammatory polyarthritis that has many features similar to human rheumatoid arthritis. In rheumatoid arthritis, pregnancy leads to amelioration of the disease while exacerbation develops after delivery. We used the CIA model to elucidate the role of pregnancy on disease and vice versa. The onset of arthritis in pregnant mice was delayed in the B10.RIII strains immunized with native porcine type II collagen 7-12 days prior to syngeneic [B10.RIII (susceptible to CIA) X B10.RIII] and allogeneic (B10.RIII female X B10.K male that are CIA resistant) pregnancy. In contrast, when mice were immunized on days 1-6 of pregnancy, the onset of arthritis was earlier as compared with controls. In addition, once the mice developed CIA after delivery, the disease showed markedly rapid progression as compared to the control immunized group. Humoral immune responses to type II collagen showed significantly decreased levels on day 14 (at late stage of pregnancy) both in syngeneic and allogeneic postmating immunized pregnant mice. The same effect was also seen in allogeneic premating immunized pregnant mice on day 21 (at mid-stage of pregnancy). The levels of these antibodies increased after delivery. Subclasses of IgG1 and IgG2a antibodies to type II collagen were suppressed during pregnancy. In the pseudopregnant group, these antibodies showed decreased levels on day 14, but did not differ from the control groups on day 21 and 28. Some immunoregulatory changes may play a role in these alterations in pregnant arthritic mice. In comparison to the effects of syngeneic (susceptible X susceptible) pregnancy on CIA, allogeneic (susceptible female X resistant male) pregnancy seemed to be beneficial for the affected individuals. Litter size and mean birth weight were not affected by immunization of type II collagen. After onset of CIA, both syngeneic and allogeneic matings failed to produce offspring in arthritic female mice. The estrus cyclicity was highly disturbed in arthritic female mice and gonadotropin stimulation in arthritic mice induced significantly less ova in oviducts and maturing follicles as compared to nonarthritic controls. Immunological factors yet to be elucidated may be involved in this ovarian dysfunction.
We studied 20 patients with a history of multiple pregnancy losses who had more than one partner for differences in reproductive efficiency with different partners. On the basis of obstetric history, patients were classified as primary (no children) or secondary (abortions after having children or stillbirths) aborters with their mates. Of 16 women diagnosed as primary aborters, 5 were primary aborters with their first mates and 11 with their second; one became a secondary aborter with her second partner. Five women were secondary aborters with either mate, and one of these was a secondary aborter with both. In no instance did a secondary aborter become a normally reproducing woman. These findings indicate that pregnancy failure in primary aborters may be due to compatibility between mating partners and that secondary aborters seem to manifest an innate aberration.
To assess the occurrence of premature ovarian failure, the age-specific incidence rates of natural menopause were determined for a cohort of 1858 women born between 1928 and 1932. These women were identified as Rochester, Minnesota residents in 1950 and were followed for date and type of menopause. A total of nine experienced natural menopause before age 40 years, which represents a 1% risk of natural menopause to age 40. The annual incidence rates of natural menopause per 100,000 person-years were ten for ages 15 to 29 and 76 for ages 30 to 39. In the age group 40 to 44, the incidence of natural menopause increased greatly to 881 per 100,000 person-years at risk.
Use of glycerol and the protease inhibitor phenylmethylsulfonyl fluoride resulted in a fourfold increase in the yield of androgen receptor from human neonatal foreskin and a tenfold increase in stability of this receptor. The general physical properties of the androgen-binding component isolated from the cytosol of human neonatal foreskin were found to be consistent with those previously reported for androgen receptors. The synthetic androgen methyltrienolone (R1881) was bound with high affinity (a mean dissociation constant of 0.51 nmol/L) and low capacity (5.6 fmol/mg of protein); maximum binding required 4 hours. Affinity of the receptor was highest for R1881 followed by dihydrotestosterone, testosterone, and progesterone. 17 beta-Estradiol showed little or no competition. The receptor exhibited a change of sedimentation coefficient from 8S to 4S upon treatment with 0.1 mol/L potassium chloride. Isoelectric focusing demonstrated the existence of two molecular species with apparent isoelectric points of 7.2 and 5.7.
Two studies have suggested that the risk of rheumatoid arthritis in women using oral contraceptives is less than half that of nonusers. When a third study from the Mayo Clinic failed to confirm these findings, it was criticized for inclusion of ineligible subjects, misclassification of oral contraceptive use, and inadequate statistical power. Recent expansion of the Mayo Clinic's data resources provided a unique opportunity to resolve the controversy, and a new population-based case-control study was undertaken. In comparison with the previous study, the new investigation had 2.2 times as many eligible cases and more complete ascertainment of oral contraceptive use via access to the records of Planned Parenthood of Minnesota. Comparing any prior use of oral contraceptives with never having used them, the relative risk of rheumatoid arthritis estimated from 182 cases and their 182 matched controls was 1.1 (95% confidence interval 0.7 to 1.7). The relative risk for current use was 1.3 (95% confidence interval, 0.7 to 2.4). The lack of a protective effect was independent of age, disease severity, and disease end point (date of confirmed diagnosis or symptom onset).
A total of 100 mature oocytes from 13 consecutive patients were randomly assigned from each patient to one of two treatment groups (n = 53 for group 1, n = 47 for group 2). Group 1 oocytes were incubated throughout the culture periods in medium supplemented with 7.5% homologous patient serum. Group 2 oocytes were treated similarly, except the serum supplement was of fetal cord origin. End points for examination included fertilization frequency, normality of fertilization, stage of embryonic development at two time periods, and quality of embryonic development at two time periods. None of the end points examined revealed significant differences between patient serum and fetal cord serum.
Preliminary results of a case-control study suggest that CC or factors closely associated with CC therapy (or both) may increase the risk of ectopic pregnancy. It is hoped that these results will stimulate further research for more explicit evaluation of the role of CC and LPD in the etiology of ectopic pregnancy.
To determine whether changes in circulating levels of neuropeptides are associated with symptoms of premenstrual syndrome (PMS), 20 women with the diagnosis of PMS and 20 asymptomatic subjects were studied. The premenstrual beta-endorphin levels were significantly lower in PMS patients (P = 0.0001). The decrease in beta-endorphin levels during the luteal phase, compared with the follicular phase, in PMS patients was also significant (P = 0.0002). Neurotensin, human pancreatic peptide, vasoactive intestinal polypeptide, gastrin, and bombesin-like immunoreactivity levels did not reveal significant changes between days 7 and 25 in patients with PMS.
In this report, we describe a simple, rapid biopsy-steroid metabolism assay that is applicable to any steroid tissue system. It consists of mincing the sample, tissue culture incubation, extraction of the steroids and their metabolites from the tissue, and fractionation of the metabolites by high-pressure liquid chromatography (HPLC). Radioimmunoassay is used to verify the elution patterns of certain steroids. Studies of the metabolism of [3H]progesterone in the avian oviduct showed the generation of metabolites that eluted from the HPLC system in a pattern similar to androgens, estrogens, and glucocorticoids. Studies of the metabolism of [3H]testosterone in the human foreskin showed the production of metabolites that eluted from the HPLC system similar to 5 alpha-dihydrotestosterone and 5 alpha-androstane-3,17-dione (androstanedione) from the parent [3H]testosterone. In the production of the metabolite that eluted as androstanedione in samples of foreskin from normal subjects, a significant (P less than 0.001) correlation was found with the age of the donor. Preliminary studies of patients with hypospadias showed a significant (P less than 0.005) decrease in the production of "androstanedione" compared with that in normal subjects. Because of the wide range in rates of metabolism of testosterone in the patients with hypospadias, the effect of age does not seem to be the sole determinant of a low rate of metabolism in these patients. Some samples of hypospadias foreskin had a decreased rate of production of a metabolite that eluted as dihydrotestosterone in comparison with normal foreskin, even when the age of the donor was considered. The assay described herein should be applicable to any surgical biopsy specimen and to all steroids.(ABSTRACT TRUNCATED AT 250 WORDS)
The presence of circulating antibodies to the ovary in serum samples from women with premature ovarian failure suggests that an autoimmune mechanism is a factor in the pathogenesis of this disorder in some women. Sera from 110 women with elevated serum levels of gonadotropins, low serum levels of estrogens, normal karyotypes, and amenorrhea before the age of 35 years were investigated for the presence of antibodies to the ovary. Of the total sera from these 110 patients with premature ovarian failure, 30 (27%) had results that were positive for the presence of circulating antibodies to ovary.
Patients with an ectopic pregnancy were studied for documentation of the site of ovulation in order to determine the frequency with which controlateral ovulation and ovum transport occurs. Analysis of data on 135 patients in whom the site of ovulation was documented at the time of surgery and on 24 patients who were studied ultrasonically before surgery indicates that contralateral ovulation and ovum transport occurs in at least a third of ovulatory events.
Sixty-three pregnant patients were treated for primary carcinoma of the breast at the Mayo Clinic between 1950 and 1980. These patients had a greater incidence of nodal metastasis and scirrhous histopathologic factors than did non-pregnant patients with a malignant condition of the breast. The five year survival rate of pregnant patients with localized malignant growths of the breast was 80 per cent. Improved survival time was not demonstrated for patients who terminated the pregnancy.
A case-control study was performed to determine the relationship between galactorrhea and the use of oral contraceptives as well as other risk factors. The cases included all 109 Olmsted County residents who satisfied the diagnostic criteria for galactorrhea between 1970 and 1980. Control subjects were selected from a sampling frame of all medical registrations and matched to the cases by age, year, and residency. Pituitary adenomas were strongly associated with galactorrhea, as the relative risk was 23.2 (95% confidence interval 2.0 to 90.0). In galactorrhea cases without pituitary adenomas there was an association with oral contraceptives (ever use versus never use), as the relative risk was 2.3 (95% confidence interval 1.3 to 4.4). Among current users of oral contraceptives, the risk of galactorrhea was not increased, but there was a trend of diminishing risk with duration of use. The estimate of relative risk was 3.1 after discontinuation of oral contraceptive use and was highest for the first year after discontinuation (5.5), compared with a year or more after discontinuation (2.1). Thus, galactorrhea was associated with the cessation of oral contraceptives.
To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant = 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons.
The present study identified and characterized an androgen-binding protein in human testicular tissue. Human testes were homogenized in dilute Tris buffer containing thioglycerol, phenylmethylsulfonylfluoride, and molybdate. The supernatant (termed cytosol) was incubated with radiolabeled androgen methyltrienolone (tritium-labeled R1881), and nonspecific binding was determined by adding 100-fold excess of unlabeled R1881 together with [3H]R1881 to cytosol. Specific binding with saturation at 24 hours was observed. Scatchard analysis of the specific binding with the use of increasing concentrations of [3H]R1881 alone and [3H]R1881 plus 200-fold excess unlabeled R1881 demonstrated a high-affinity (dissociation constant = 2.18 X 10(-10) mol/L), low-capacity (2924 molecules per cell) class of binding sites. A second class of lower-affinity sites was identified with a dissociation constant equaling 1.2 X 10(-8) and 26,300 molecules per cell. The bulk of the higher-affinity class of sites was precipitated at 35% ammonium sulfate. In competitive binding assays, dihydrotestosterone and testosterone greatly diminished binding to this high-affinity class of sites. Progesterone also diminished binding but to a lesser degree. Estradiol, estriol, and estrone failed to compete for these sites. Analysis of the receptor, using sucrose gradients, revealed a major peak in the 4S region and a small peak at 8S. A similar high-affinity (dissociation constant = 4.28 X 10(-9), low-capacity (4860 molecules per cell) binding protein was identified in purified nuclei. Binding to nuclear chromatin was demonstrated in the cell-free binding assay, and nuclear binding was further illustrated in the biopsy assay of intact tissue, suggesting translocation in vivo. These properties are characteristic of the androgen receptor and suggest that human testis is a target tissue for androgen, as has been found in animal tissue.