Arie Birkenfeld

Artificially Induced Endometrial Cycles and Establishment of Pregnancies in the Absence of Ovaries

In eight women with ovarian failure, we induced histologically normal endometrial function during a preparatory cycle consisting of sequential administration of estrogen and progesterone. During a subsequent cycle, endometrial stimulation was synchronized with surrogate-embryo transfer performed on days 16 to 21. Among the eight women, two pregnancies were established by embryo transfer on days 18 and 19. In both women, ovarian tissue was absent, and these patients therefore serve as an in vivo model for the isolated effects of estrogen and progesterone on implantation and maintenance of pregnancy. Treatment with exogenous estrogen was mandatory up to the 11th week of gestation, and treatment with progesterone until the 18th to 22nd weeks. We conclude that it is biologically feasible to simulate the essential hormonal and endometrial milieu of a fertile menstrual cycle and early gestation solely by the administration of estrogen and progesterone. Days 18 to 19 of the cycle are recommended for successful embryo implantation with this treatment program.

Direct correlation between plasma renin activity and severity of the ovarian hyperstimulation syndrome

Plasma renin activity (PRA) and aldosterone were measured throughout the luteal phase in 21 anovulatory patients who developed ovarian hyperstimulation syndrome (OHSS) during menotropin induction of ovulation. The pattern of PRA in hyperstimulated cycles is characterized by a midluteal peak, which declines to normal in the late luteal phase in nonconceptual cycles, whereas a sustained elevation of PRA occurs in conceptual cycles. Midluteal PRA is significantly (P less than 0.001) elevated in patients with OHSS compared with controls. In the mild form of the disease, the median of PRA is 7.5 (range 6 to 11) ng angiotensin I (AI)/ml/hr, significantly higher than the median for controls, 3.0 ng AI/ml/hr (range, 1.4 to 5). In moderate OHSS, PRA was 24.5 (range, 10 to 40) ng AI/ml/hr, whereas, in the severe form of OHSS, PRA was 55.0 (range, 29 to 95) ng AI/ml/hr. A significant correlation (P less than 0.05) was demonstrated between PRA and either progesterone or 17 beta estradiol (E2). The renin-angiotensin cascade is implicated in new vessel formation. Angiogenesis itself is associated with a rapid increase in capillary permeability. The recent demonstration of high plasma renin-like activity in human follicular fluid and the present observation of high PRA in patients with OHSS may imply that the locally active renin angiotensin system, through induction of new vessel formation and increase in capillary permeability, may have a casual relationship to the ovarian enlargement and extracellular fluid accumulation that are the hallmarks of OHSS.

Risk factors and prognostic variables in the ovarian hyperstimulation syndrome

This study was undertaken to clarify discriminative roles of multiple epidemiologic, hormonal, and biophysical variables for causation of ovarian hyperstimulation syndrome. Three hundred ninety-six patients with anovulatory infertility had ovulation induction with human menopausal gonadotropin throughout 1822 treatment cycles; 54 cycles (3%) were complicated by ovarian hyperstimulation syndrome. Early follicular serum estradiol and prolactin levels were higher in this group than in controls: 75.5 versus 46.2 pg/ml and 18.5 versus 11.7 ng/ml, respectively (p less than 0.01). On the day of human chorionic gonadotropin administration (day 0) the mean serum estradiol level was 1047 +/- 381 in the group with ovarian hyperstimulation syndrome and 719 +/- 339 pg/ml in controls (p less than 0.0001). In all follicular sizes and in all grades of ovarian hyperstimulation syndrome there was a tendency for more recruited follicles, with significantly more small follicles (12 to 14 mm) present on day 0 in all grades of ovarian hyperstimulation syndrome than in controls. Stepwise logistic regression performed on 22 variables identified a high-risk group for this syndrome; the major features are illustrated by young, lean patients who, after relatively few ampules of human menopausal gonadotropin, develop high estradiol levels and multiple small follicles.

Menopause-related Oral Alveolar Bone Resorption: A Review of Relatively Unexplored Consequences of Estrogen Deficiency

OBJECTIVE The alveolar processes of the maxilla and mandible provide the bony framework for tooth support. Osteoporotic changes of these bones may directly affect tooth stability and retention. This report reviews studies that have evaluated the relationship between systemic osteoporosis and oral alveolar bone mass as well as the effect of estrogen use on oral alveolar bone and tooth retention. DESIGN Ten years (1989-1998) literature review. RESULTS Studies reviewed demonstrate a positive correlation between systemic bone mass and systemic osteoporosis to oral bone resorption. Estrogen replacement therapy affects oral bone in a manner similar to the way it affects other sites. CONCLUSIONS It is evident that postmenopausal estrogen users may retain more teeth after menopause. Sustained oral health and better tooth retention are potentially additional benefits for hormone replacement therapy users after menopause.

Fryns syndrome: A predictable, lethal pattern of multiple congenital anomalies

Fryns syndrome is a unique pattern of lethal multiple congenital malformations with variable expression. A family in which all four sibs conformed to Fryns syndrome is detailed and substantiates the criteria for definition of the syndrome; perinatal mortality, hypoplastic lungs, and facial deformities should be highly suggestive of the syndrome. The addition of a strong family history, diaphragmatic hernias, distal limb deformities, and early onset of polyhydramnios with subsequent premature delivery should definitely confirm the diagnosis.

Fetal response to vibratory acoustic stimulation in periods of low heart rate reactivity and low activity

The fetal response to vibratory acoustic stimulation during periods of low fetal activity and low fetal heart rate reactivity was studied in 10 healthy pregnant women at term. In each case, two periods of low reactivity were studied. Consecutive cases alternated: The vibratory acoustic stimulus was applied 10 minutes after the first nonreactive period in half of the cases; the remainder were stimulated during the second nonreactive period. The unstimulated period served as a control. After vibratory acoustic stimulation the baseline fetal heart rate, the mean number of fetal heart rate accelerations, and, the number of fetal movements were significantly increased with values in the control nonstimulated periods (p less than 0.0001). This consistent response to vibratory acoustic stimulation may prove to be clinically useful in altering periods of low reactivity observed during nonstress testing of normal fetuses.

Gynecologic manifestations of Sjögren's syndrome * ** *

OBJECTIVE Sjögrens syndrome is a chronic, inflammatory autoimmune disease in which the salivary and lacrimal glands are progressively destroyed by lymphocytes and plasma cells. Because women are affected 10 times more often than men, we studied gynecologic manifestations of Sjögrens syndrome. STUDY DESIGN One thousand questionnaires were sent to women with Sjögrens syndrome in New York, New Jersey, Connecticut, and Pennsylvania. Five hundred thirty-nine women responded. RESULTS Women with Sjögrens syndrome reported significant vaginal dryness. There was no relationship of Sjögrens syndrome to either the incidence of infertility or miscarriage, although the 4% incidence of congenital anomalies in offspring was relatively high. Of the congenital anomalies, nine of 19 (47%) were cardiac. A long menstrual cycle (> 35 days) was associated with infertility and neuropathy. CONCLUSIONS The vaginal dryness in women with Sjögrens syndrome is not surprising, because the nasal and esophageal mucosae are also dry in this disorder. The relationship of infertility to a long menstrual cycle may simply indicate the presence of ovulatory dysfunction or inadequate luteal phase unrelated to Sjögrens syndrome. The relationship of neuropathy to a long menstrual cycle may be related to repeated, prolonged estrogen or progesterone exposure during the long cycles or to involvement of hypothalamic-pituitary-ovarian function.

The effect of clomiphene citrate on blastocyst development and implantation in the rabbit.

SummaryThe induction of ovulation with clomiphene citrate (CC) in human patients results in a high ovulation rate but achieves a relatively low pregnancy rate. To clarify the possible role of CC in interfering with the normal reproductive physiology and embryology, we have used our rabbit model and transferred 4-day-old blastocysts from untreated donors to CC-treated pseudopregnant recipients and from CC-treated donors to untreated pseudopregnant recipients to study embryonic development and implantation. Each group was further subdivided into two subgroups, one receiving CC before and the other after ovulation. CC was administered subcutaneously in three consecutive doses of 10 mg/kg body weight. Ovulation was induced with pregnant mare serum gonadotropin (PMS) and human chorionic gonadotropin (hCG).The implantation rate of the control group, evaluated on day 8 of pregnancy, reached 62.0%. When recipients were treated with CC before ovulation, implantation rate was reduced to 18.8% (P < 0.0002), and to 20.0% (P < 0.003) when CC was administered after ovulation. The implantation rate of blastocysts transferred from donors, treated before ovulation, is 22.2% (P < 0.0055), however, reached 70.8% when treatment was started after ovulation. All implantations were analysed microscopically and showed normal morphological features.Our results demonstrate a potential multiple effect of CC, first on the endometrium by altering its receptivity for the implanting conceptus, second, on tubal physiology by altering egg transport, and finally on ovum maturation before ovulation interfering with development of blastocysts. These parameters may all result in rapid decrease in establishment of implantations and in turn in very low pregnancy rates.

Successful Full-Term Pregnancy in Familial Mediterranean Fever Complicated with Amyloidosis: Case Report and Review of the Literature

Pregnancy during familial Mediterranean fever complicated with amyloidosis and severe nephrotic syndrome is rare and may cause several maternal and fetal complications. Asymmetrical intrauterine growth retardation, superimposed preeclampsia, thromboembolic phenomena, resistant anemia and renal failure only partially represent the possible complications. A successful outcome of a full-term pregnancy is presented and the efficiency of colchicine, a high protein diet, acetylsalicylic acid and dipyridamole is discussed.

Second primary genital malignancies associated with endometrial cancer.

SummaryEpidemiological data on Israeli patients with second primary genital malignancies associated with endometrial cancer is presented. During the 7 years of study, 29 (2.9%) of 1007 patients with endometrial cancer had additional primary malignancy involving the genital organs. Of these, there were 25 (2.5%) ovarian and 4 (0.4%) cervical malignancies. The occurrence of a second malignancy was related to ethnic origin. The ratio of European/American to Asian/African Jewish descendants was 8.7 to 1. A significantly greater than expected incidence of ovarian and cervical malignancy was detected in the endometrial cancer patient (P < 0.0001). The prognosis was mainly influenced by the clinical staging of disease at the time of diagnosis. Recognition of the fact that second primary cancers occur at a higher than expected frequency in patients with endometrial cancer, offers an opportunity for their early detection.