Joseph Itskovitz

Prorenin as a reproductive hormone. New form of the renin system

Prorenin, the biosynthetic precursor of renin, is synthesized by the kidneys. Herein is reviewed recent evidence that the ovaries also secrete prorenin. It was found that prorenin is present in mature human ovarian follicular fluid in extremely high concentrations and that plasma prorenin levels increase transiently in blood during the menstrual cycle at the time of ovulation. No change in plasma active renin levels occurs at this time. Plasma prorenin level also increases 10-fold in pregnant women very soon after conception. The ovaries are apparently the source of this rise, since plasma prorenin levels did not increase in a pregnant woman with ovarian failure who received a donor egg. All of these changes in plasma prorenin levels appear to be caused by gonadotropic hormones. These results suggest a role for ovarian prorenin in human reproductive function. They may have relevance to studies of female infertility, birth control, and toxemia of pregnancy. They also suggest that a renin system exists that is regulated by changes in prorenin.

Ovarian prorenin-renin-angiotensin system.

Renin is classically considered to be an enzyme that is synthesized by the kidneys and secreted into the circulation where it affects angiotensin production. We review here recent evidence that suggests the existence of an extra-renal renin system, the ovarian prorenin-renin-angiotensin system, which may be linked to reproductive function. Prorenin, the inactive form of the enzyme renin, is present in the fluid of mature human ovarian follicles in extremely high concentrations; however, only 1 per cent of the renin in follicular fluid is in the active form. Plasma prorenin increases about 2-fold at midmenstrual cycle at the time of the LH surge, and the peak of prorenin is sustained for about 2 days. No change in plasma active renin levels occurs at this time. Administration of hCG to women whose ovaries have been stimulated with gonadotropins results in much higher plasma prorenin levels and the height of prorenin response is directly related to the number of mature follicles. Plasma prorenin also increases 10-fold during the early stages of pregnancy. It begins to rise on days 8 to 12 after embryo transfer, in parallel with the rise in endogenous hCG. The ovaries are the apparent source of the increase in plasma prorenin in early pregnancy since no such increase in prorenin occurred in a woman with ovarian failure who conceived after receiving a donor egg. These results suggest that prorenin is synthesized and secreted by the mature ovarian follicle and by the corpus luteum in response to LH/hCG. They also suggest that an ovarian renin system exists that is regulated by changes in prorenin.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular responses to hypoxemia in sinoaortic-denervated fetal sheep.

Fetal cardiovascular response to acute hypoxemia is characterized by bradycardia, hypertension, and redistribution of cardiac output. The role of aortic and carotid chemoreceptors in mediating these responses was examined in eight sinoaortic-denervated and nine sham-operated fetal lambs. Blood gases, pH, heart rate, arterial pressure, and blood flow distribution were determined before and during hypoxemia. In intact fetuses, heart rate fell from 184 ± 12 to 165 ± 23 beats/min (p < 0.01) but increased from 184 ± 22 to 200 ± 16 beats/min (p < 0.05) in the sinoaortic-denervated fetuses. Intact fetuses showed an early hypertensive response to hypoxemia, whereas the sinoaortic-denervated fetuses developed a delayed, progressive rise in blood pressure. In both groups, fetal cardiac output and umbilical blood flow were maintained; cerebral, myocardial, and adrenal blood flow increased, and pulmonary blood flow decreased. Peripheral blood flow decreased 39% (p < 0.001) in intact fetuses but was maintained in sinoaortic-denervated fetuses. Vascular responses to hypoxia in the brain, heart, adrenal, and lungs are regulated primarily by direct local effects. During hypoxemia, peripheral chemoreceptors mediate bradycardia and peripheral vasoconstriction but do not appear to be crucial for immediate fetal survival. (Pediatr Res 30: 381–385, 1991)

Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during, and after treatment *

Pituitary sensitivity to a gonadotropin-releasing hormone (GnRH) challenge test before, during, and after GnRH antagonist administration was compared in four ovariectomized female monkeys receiving GnRH antagonist intramuscularly (IM) at increasing doses of 0.3, 1.0, and 3.0 mg/kg/day over 9 days. Three days before and 3 days after treatment, monkeys received vehicle alone. On experiment days 4, 7, 10, 13, and 16, 100 micrograms of GnRH was administered intravenously (IV) and blood drawn at 0 and 30 minutes. Before treatment, tonic follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were 248 +/- 105 and 178 +/- 31 ng/ml, respectively; after 0.3 mg/kg/day of GnRH antagonist, FSH and LH decreased to 30 +/- 6 and 41 +/- 4 ng/ml, respectively. After treatment with either 1 mg/kg/day or 3 mg/kg/day of GnRH antagonist, both gonadotropins were undetectable in serum. Monkeys with lower initial levels of gonadotropins were suppressed by 48 hours after GnRH antagonist, while those with higher tonic gonadotropins were suppressed 6 days later (FSH: r = 0.992; LH: r = 0.833). The data show that initial physiologic status is predictive of the rapidity of the suppression response induced by a GnRH antagonist and that, after achieving pituitary suppression, responsivity to an IV GnRH challenge test may be restored before normal tonic FSH/LH secretion is regained.

Effects of naloxone on fetal circulatory responses to hypoxemia

The effects of opiate receptor antagonism on the fetal cardiovascular response to hypoxemia were examined by means of the radionuclide-labeled microsphere technique. Heart rate, blood pressure, and cardiac output were measured during baseline periods, during hypoxemia, and before and after infusion of either naloxone (1 mg/kg) or an equivalent volume of 0.0% saline solution. Seventeen fetal sheep were subjected to maternal hypoxemia by allowing the ewes to breathe 10% oxygen (3% carbon dioxide, 87% nitrogen). The fetuses responded with bradycardia (p less than 0.002 compared with control), increased blood pressure (p less than 0.002 compared with control), and no significant change in combined ventricular output or placental blood flow. After naloxone, the bradycardia increased by 10% (p less than 0.001), and both combined ventricular output and placental blood flow fell by 20% (p less than 0.01 and p less than 0.01, respectively). The fetal bradycardic response to naloxone was reversible with atropine. In fetuses with normal oxygenation of the blood (normoxemic), naloxone had no significant effect on heart rate and blood pressure. These data indicate that endogenous opiates (e.g., endorphin and enkephalin) are important in regulating the fetal circulation during hypoxia, and that the effects of opiate receptor antagonism may be mediated through the autonomic nervous system.

Transplacental passage of a progesterone antagonist in monkeys

The progesterone antagonist RU 486 dramatically increases myometrial contractility of the pregnant uterus, making it a potential adjunctive therapy for labor induction or therapeutic pregnancy termination. Sixteen female cynomolgus monkeys were studied during the second or third trimester of pregnancy. Hysterotomies were performed with the animals under anesthesia, providing access to the intact placental vasculature. RU 486 (25 mg) was injected intravenously into the mothers. Serial blood samples were drawn from the maternal and fetal-placental compartments for a period of 2 hours. RU 486 achieved a gradient equilibrium between the maternal and fetal-placental circulation within 5 minutes, suggesting free passage by simple diffusion. The clearance kinetics of immunoreactive RU 486 are consistent with an open three-compartment system in mother and fetus. The fetal-placental index decreased from 31.2% to 17.8% between the second and the third trimester of pregnancy. There was no acute toxicity of the RU 486 noticed during the experimental course.

Reduction of the number of embryos in a multiple pregnancy: quintuplet to triplet

The technique for reduction of the number of embryos was applied in a patient who conceived following IVF and transfer of six embryos. On the 10th week of gestation, the number of embryos was reduced from five to three by an U/S-guided intra-uterine procedure. Two healthy girls and a boy were delivered in the 36th week by cesarean section. No trace of the other two fetuses was found. The moral and technical aspects of partial preventive termination of multiple pregnancy are discussed.

Endocrine basis for the initiation, maintenance and termination of pregnancy in humans

Channels of hormonal communication between the embryo and the mother are established early in the conceptual process. The preimplantation embryo exerts local uterine and systemic effects on the maternal organism to provide a suitable environment for embryonic development, to enable the development of a receptive endometrium for implantation, and to maintain corpus luteum function. In primates, implantation can be induced with progesterone alone if the proliferative effects of estrogens on the endometrium have already been achieved; estrogens may have a priming effect for progesterone on the endometrium, but it is not obligatory for implantation. Progesterone secretion from the corpus luteum is essential for the maintenance of early pregnancy until the placenta takes over the major role of steroidogenesis. This luteo-placental shift is completed at about the 50th day of human gestation. Withdrawal of progesterone effects by the administration of the competitive progesterone antagonist, RU 486, within 24 days after conception will terminate 85% of human pregnancies. Other nonsteroidal functions of the corpus luteum have been recently suggested. Relaxin and prorenin are peptides secreted by corpus luteum of pregnancy but their role remains putative at the present time.

Basic principles and clinical applications of the transvaginal Doppler duplex system in reproductive medicine

ConclusionNew technological advances in the field of ultrasound imaging and in Doppler signal acquisition and analysis help to open new fields of investigation in reproductive medicine. One such example is the recent introduction of the transvaginal Doppler duplex system, which can be applied as a sensitive, noninvasive “flow probe” to evaluate hemodynamic changes in pregnant and nonpregnant patients. Another important development is the application of Doppler color flow mappping, which facilitates vessel recognition and localization. Such instruments are expensive at present and are mostly limited for research purposes. Further developments are likely to emerge once new instruments and new methods of data analysis become available. Further increases in image resolution and improved Doppler signal generation and processing will enable more accurate flow measurements. Another important field is invasive flow measurement, which could be developed for intraoperative and intravascular investigations, based on specialized probes and catheter-mounted transducers. At present further investigations are required for defining the normal ranges in the population and for establishing abnormal patterns. Once causative mechanisms are defined, various treatments may be offered, while monitoring the changes using the techniques described here.

The Ovarian Prorenin‐Angiotensin System a

Recent evidence suggests that prorenin and other active components of the renin-angiotensin system may be linked to ovarian physiology. Prorenin, the inactive form of the enzymatically active renin, is present in the fluid of mature human ovarian follicles in concentrations more than 10 times higher than that found in the plasma of women undergoing ovarian stimulation. Only 1% of the renin in follicular fluid is in active form. Concentrations of prorenin in fluid of immature follicles are lower than levels detected in concomitantly aspirated mature follicles. Study of prorenin levels disclosed a positive correlation to testosterone and E2 in fluids of mature follicles. Plasma prorenin increases about twofold at midcycle at the time of the LH surge; the peak of prorenin is sustained for about 40 hours. In patients undergoing ovarian stimulation for IVF, hCG administration results in much higher plasma prorenin levels and the height of prorenin response is directly related to the number of mature follicles. It peaked 4 to 6 days after hCG injection and then fell, close to baseline, by about 12 days after hCG administration. Examination of the time course of hormonal changes in response to hCG revealed a temporal relationship between prorenin and both plasma E2 and progesterone. In women who conceived, prorenin began to rise again on days 8 to 12 after embryo transfer when endogenous hCG was detected in the blood. No such changes in prorenin occurred in women with ovarian failure who conceived after transfer of a donor egg. These findings indicate that prorenin is produced by the mature follicle and the corpus luteum in response to LH/hCG. Since angiotensin II affects intracellular calcium and phospholipase activity, there are many potential roles for prorenin via angiotensin II action. Putative actions of the ovarian renin system may include control of oocyte maturation, ovulation, ovarian blood flow, and ovarian steroid biosynthesis. Future work to elucidate the function of this new renin system may have relevance to many basic and clinical aspects of human reproduction.