Jonathan W.T. Ayers

Major histocompatibility complex antigens, maternal and paternal immune responses, and chronic habitual abortions in humans.

Women with recurrent consecutive spontaneous abortions of unknown etiology compared with those with recurrent spontaneous abortions of known etiology had a significantly, increased frequency of sharing HLA antigens at the A, B, and D/DR loci with their spouses. This major histocompatibility complex (MHC) homozygosity was generally associated with female (responder) and male (stimulator) hyporeactivity in mixed lymphocyte culture reactions. The results indicate that MHC homozygosity between spouses is associated with postfertilization pregnancy wastage in humans.

Luteal phase dysfunction in endometriosis: elevated progesterone levels in peripheral and ovarian veins during the follicular phase

Endometriosis has been associated with corpus luteum inadequacy and abnormalities of luteal phase progesterone (P) secretion. In this study, abnormal luteolysis, as a second factor of luteal dysfunction, was assessed in 13 women with endometriosis and 25 control patients by measurement of ovarian vein estradiol (E2) and P during the follicular phase. The results reveal that women with endometriosis have (1) significantly lower ovarian vein E2, (2) significantly higher both peripheral and ovarian vein P, and (3) threefold higher P/E2 ratios than controls during the follicular phase. These data support the concept of continued P production from an active corpus luteum well into the follicular phase of the following cycle in women with endometriosis. Failure of adequate luteolysis is a second aspect of luteal dysfunction in endometriosis and strongly supports the growing body of data confirming ovulatory asynchrony in the minimal; endometriosis infertility syndrome.

The effect of insulin on aromatase activity in isolated human endometrial glands and stroma

Hyperinsulinemic states have been associated with an increased incidence of estrogen-dependent endometrial neoplasia. To study the effect of insulin on the ability of endometrium to aromatize androgens to estrogens, late proliferative endometrium was obtained from normally cycling women at the time of indicated surgery, separated into component glands and stroma, and grown to confluence. Separated gland and stromal cultures were incubated in triplicate with increasing insulin concentrations and epidermal growth factor. Aromatase activity was assayed by the production of tritiated water from tritium-labeled androstenedione. The activity was noted to increase proportionally with increasing concentrations of insulin greater than 10 U/ml, and the effect was specific. These data suggest the following conclusions: (1) Insulin stimulates aromatase activity in both endometrial glands and stroma; (2) hyperinsulinemia may predispose to endometrial neoplasia by enhancing endogenous endometrial estrogen production.

Diagnostic considerations in virilization: iodomethyl-norcholesterol scanning in the localization of androgen secreting tumors.

Accurate localization of the source of androgen hypersecretion is critical to the appropriate surgical or medical management of women with virilization. Seven patients with virilization and hyperandrogenism of various causes were evaluated with the use of sequential studies: (1) testosterone stimulation and suppression tests; (2) computerized tomography (CT); (3) selective venous catheterization; and (4) 131 I-iodomethyl-norcholesterol (NP-59) scintigraphy. Comparison of the diagnostic accuracies of these localization studies with the ultimate diagnoses in this group of virilized women showed that: (1) endocrinologic suppression/stimulation studies are of limited value in tumor localization and helpful only in patients with steroidogenic enzyme deficiencies; (2) both selective catheterization and CT scanning may provide spurious localization data; and (3) NP-59 scintigraphy, by depicting both the anatomic localization and functional androgen hypersecretion, may provide the most significant localization data in the evaluation of patients with virilizing syndromes.

The "luteal breast": hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.

The pathophysiology, malignant potential, and hormonal therapy for benign breast disease remain controversial. This report investigates the anatomic and endocrinologic correlates of luteal phase mastodynia patients, compared with asymptomatic control subjects. Objective sonographic evidence of fibrocystic disease (FCD) was found in one-half of both mastodynia and control groups. Endocrine abnormalities observed in the mastodynia group included (1) significantly lower luteal phase progesterone and (2) prolactin hyperresponsiveness to thyroid-releasing factor. The presence or absence of anatomic FCD was not correlated with endocrine abnormalities. These data suggest that (1) cyclic mastalgia may be the end result of a dyshormonal milieu resembling the inadequate luteal phase; (2) FCD may be hormonally independent; and (3) cyclic mastalgia and FCD are different, if often coexistent, factors in benign breast disease syndromes.

Differential response to adrenocorticotropin hormone stimulation in polycystic ovarian disease with high and low dehydroepiandrosterone sulfate levels

The relative contributions of the ovary and the adrenal gland to androgen overproduction in polycystic ovarian disease (PCOD) remain controversial. In this investigation, patients with proven PCOD were divided into two groups, (1) those with low dehydroepiandrosterone sulfate (DHEAS) levels and (2) those with high DHEAS levels, and compared with controls for their response to adrenocorticotropin hormone (ACTH) stimulation. Significant differences in weight, degree of menstrual disturbance, and basal progesterone levels distinguished the two groups with PCOD. Although no discrete enzyme block was unmasked by ACTH, marked differences in steroid production ratios were apparent between the low and high DHEAS PCOD groups. These results suggest that in PCOD with high DHEAS (1) substantial differences in adrenal steroidogenesis pathways occur, (2) increased progesterone as well as inappropriate estrogen feedback may contribute to chronic anovulation, and (3) serum DHEAS levels may be a helpful screen in discerning those patients who have a significant adrenal component to their hyperandrogenism and may benefit from adrenal suppression alone or in combination.

Preimplantation genetic diagnosis for the Kell genotype

OBJECTIVE To use preimplantation genetic diagnosis (PGD) to achieve a Kell 1 (K1) allele-free pregnancy in couples at risk for producing a child with hemolytic disease of the newborn (HDN) caused by maternofetal incompatibility in sensitized mothers. DESIGN DNA analysis of biopsied blastomeres from cleavage-stage embryos in IVF-ET with the goal of identifying and transferring back to patients the K1 allele-free embryos. SETTING IVF program at the Reproductive Genetics Institute, Chicago, Illinois, and IVF Michigan, Rochester Hills, Michigan. PATIENT(S) Two at-risk couples with a history of neonatal death caused by HDN due to K1/K2 genotype in a male partner. INTERVENTION(S) Biopsy of single blastomeres and testing for paternal K1 allele in each embryo after standard IVF. MAIN OUTCOME MEASURE(S) DNA analysis of blastomeres indicating whether corresponding embryos were K1 allele-free for the purpose of transferring only embryos without the K1 allele. RESULT(S) Of 36 embryos tested in five cycles from two couples, 18 were predicted to be K1 allele-free. Of these, 9 were transferred, resulting in a K1 allele-free twin pregnancy and the birth of two healthy children. CONCLUSION(S) PGD of the K1 genotype resulted in the birth of healthy twins confirmed to be free of the K1 allele. PGD in couples with a heterozygous K1/K2 male partner provides an option for avoiding HDN in sensitized mothers.

Sterilization failures with bipolar tubal cautery

From a consecutive series of 105 patients undergoing bipolar tubal sterilization (BPS), ten pregnancies were reported, and a tubal patency rate of 16% was found at hysterosalpingography. There were no significant clinical variables separating the BPS failure patients from those with successful sterilization. Ninety percent of the BPS failures were intrauterine, and 90% occurred within three cycles of BPS. The results of this investigation suggest that (1) BPS tubal occlusion may be associated with an increased failure (pregnancy and tubal patency) rate; (2) the majority of BPS failures are intrauterine gestations; (3) delayed fibrosis, rather than immediate tubal destruction, may be the mechanism of BPS tubal occlusion; (4) for maximum effectiveness, patients undergoing BPS should use alternative contraception for two to three cycles; and (5) surgeons employing BPS require precise training in the application of this modality of female sterilization.

Early therapy for the incompetent cervix in patients with habitual abortion

From a thorough evaluation of 66 couples with habitual abortion (HA), 42 were found to have a widened uterine isthmus at hysterosalpingography (HSG) as their only abnormality. First trimester cervical effacement occurred in 90% of these patients. A combination of medical (progesterone [P]), and surgical (McDonald cerclage) begun during the first trimester resulted in successful term pregnancy in 35 of the 36 HA patients (97%) who were treated. The results of this study suggest that (1) functional cervical incompetence may play a major role in HA; (2) a widened uterine isthmus at HSG and first trimester cervical effacement are clinical signs that may define this group of HA; (3) early recognition and therapy for the incompetent cervix can interrupt the progression of events leading to the loss of an otherwise normally developing fetus; and (4) increased perinatal morbidity demands continuous antepartum assessment of fetoplacental integrity in these patients.

Major Histocompatibility Complex Antigens, Maternal and Paternal Immune Responses, and Chronic Habitual Abortions in Humans

Women with recurrent consecutive spontaneous abortions of unknown etiology compared with those with recurrent spontaneous abortions of known etiology had a significantly increased frequency of sharing HLA antigens at the A, B, and D/DR loci with their spouses. This major histocompatibility complex (MHC) homozygosity was generally associated with female (responder) and male (stimulator) hyporeactivity in mixed lymphocyte culture reactions. The results indicate that MHC homozygosity between spouses is associated with postfertilization pregnancy wastage in humans.