Prognostic value of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease and left ventricular dysfunction. Investigators of this Multicenter Study

Reproductive aging in women is closely tied to the loss of ovarian follicles through atresia. The sentinel endocrinologic finding is the monotropic FSH rise, associated with a decline in ovarian inhibin B secretion. Fertility becomes significantly compromised long before overt clinical signs occur, such as cycle irregularity. Compromised fertility is primarily related to oocyte dysfunction. As women with regular cycles near the end of the reproductive years, the following changes are usually manifested: 1) the selection and development of a dominant follicle occurs earlier; 2) there is earlier ovulation; 3) there is a short follicular phase and total cycle length; and 4) ovarian steroid secretion is normal. The relationships, if any, between the monotropic FSH rise, accelerated follicular atresia, shortened follicular phase, and oocyte quality remain to be determined. The next phase of reproductive aging is the perimenopause. Lack of predictability is the rule with regard to the nature and duration of the perimenopause. Long cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with periods that are hormonally indistinct from the postmenopausal state. Even after the last menstrual period, evidence of intermittent ovarian estradiol production may still be detected. Although fertility is severely compromised during the perimenopause, ovulation may occur without warning and contraception must be practiced if pregnancy is not desired. Further studies are needed to elucidate the factors contributing to oocyte abnormalities in women of advanced reproductive age, as well as the factors that determine the rate of follicle atresia and the length of the reproductive life span.     

Physicians and the medical society--between the interests and values

Macrophages may be a potential regulator of ovarian functions. The goal of this study was to determine the changes in the macrophage frequency (number of cells per unit square of tissue) during follicular growth, ovulation, and postovulatory follicular regression in chickens. Cryostat sections of ovarian stroma containing primary follicles, small white follicles, and preovulatory and postovulatory follicles of laying hens were immunostained for macrophage using mouse anti-chicken macrophage monoclonal antibody. Macrophages were observed under a light microscope and counted by a computer assisted image analyzer. The frequency of macrophages in the theca layer was significantly greater in the small white follicles than in the primary follicles (P < 0.01) and also greater in the preovulatory follicles than in the small white follicles (P < 0.01). No significant differences were observed in the macrophage frequency between the third largest and largest preovulatory follicles. In the theca layer of postovulatory follicles, macrophage frequency was significantly greater than in that layer in the preovulatory follicles (P < 0.01); however, the frequency of macrophages decreased significantly in the Day 3 postovulatory follicles as compared with Day 1 postovulatory follicle (P < 0.05). These results suggest that macrophages may play an important role in the follicular development and regression of postovulatory follicles.     

Can we define the indications for oocyte donation?

The outline of oocyte donation's indications is defined in France by the law of the 29 july 1994. A great number of situations do not pose any problem with regard to this principles: gonadal dysgenesis, premature ovarian failure, ovariectomy, castration following chimiotherapy or radiotherapy. However, others indications drive us progressively outside legal limits. What is the normal age of physiological menopause? Which threshold to justify oocyte donation for low responders? Is oocyte donation an alternative for other treatments failures? Ovocyte donation for genetic reason presents a risk of eugenic drift. Answering these questions is uneasy, though it is urgent for our patients to offer them a better uniformity.     

Should we apply assisted reproduction technology to women without limitations of age?

The decline of female fertility with increasing age is due to a physiological diminution of the ovarian reserve of follicles. Hence, a reliable evaluation of the ovarian reserve before performing assisted reproductive technology in aged women provides them and the physician with information about the actual probabilities of pregnancy. Patients aged over 38 years should be accepted in assisted reproduction programs only after confirmation of a healthy ovarian reserve. Patients aged more than 42 years, even in case of a normal ovarian reserve assessment, should be only accepted in selected cases. After 42 years until 46 of age, techniques of in vitro fertilization with oocyte donation may represent an alternative chance of pregnancy to aged women.     

PCBs as environmental estrogens: turtle sex determination as a biomarker of environmental contamination

Polychlorinated biphenyls (PCBs) are widespread, low-level environmental pollutants associated with adverse health effects such as immune suppression and teratogenicity. There is increasing evidence that some PCB compounds are capable of disrupting reproductive and endocrine function in fish, birds, and mammals, including humans, particularly during development. Research on the mechanism through which these compounds act to alter reproductive function indicates estrogenic activity, whereby the compounds may be altering sexual differentiation. Here we demonstrate the estrogenic effect of some PCBs by reversing gonadal sex in a reptile species that exhibits temperature-dependent sex determination.     

Ultrastructural changes during meiotic maturation in mammalian oocytes: unique aspects of the human oocyte

This paper reviews the process of peri-ovulatory oocyte maturation and the ultrastructural organization of the human egg and compares it with that of the mouse. The main thrust of the paper is on the human, since there are several reviews on the mouse. Both preovulatory and postovulatory events at fertilization, as well as some of the aberrant features of maturation are covered. Some changes induced by oocyte culture and cooling in the human are also included. The report attempts to focus on unique features of the human oocyte and shows a variety of ultrastructural differences between human and murine oocytes, which may well reflect differences in their physiology and biochemistry. Based on these differences and further observations on the process of fertilization of both species, particularly with respect to the inheritance of paternal centrioles, it is concluded that the mouse may not be a suitable model for the development and refinement of current procedures in human assisted reproductive technology.     

RNA synthesis in preovulatory mouse oocytes

RNA synthesis, previously shown to take place during oocyte growth, has been demonstrated throughout the growth-quiescent period preceding ovulation of the mouse oocyte. In the final 7-day preovulatory period, the level of incorporation of (5,6-3H)uridine into ovulated oocytes decreased as the interval between exposure to precursor and ovulation decreased; significant incorporation was detectable within 2 days before ovulation. Analysis of the frequency and density of label in ovarian oocytes at successive stages of meiosis in relation to the interval between adminstration of labeled precursor and collection of oocytes revealed that RNA synthesis continues up to within 2 h before GVBD.     

Endocrine mechanisms underlying reproductive toxicity in the developing rat chronically exposed to dietary lead

A dose-response study was conducted in a rat model to examine the effects of lifetime lead exposure on the development of the reproductive system and the endocrine mechanisms underlying these effects. Time-impregnated female Sprague-Dawley rats (n = 10-15/group) were exposed to lead acetate in the drinking water at levels of 0.05%, 0. 15%, or 0.45% (w/v) initiated on gestational day 5. At birth, litters were culled to four male and four female pups. Exposure of dams to lead was continued until weaning, following which, the pups continued to be exposed to lead acetate in drinking water until sacrifice. One male and one female pup from each litter were sacrificed at age 21, 35, 55, and 85 d. A significant dose-responsive decrease in birth weight and crown-to-rump length was observed in all lead-exposed litters. However, no marked effects were observed on anogenital distance/crown-to-rump length ratios. Lead exposure resulted in a delay in sexual maturity as measured by prostate weight in male pups and time of vaginal opening in female pups, which increased with lead dose. These disruptions in reproductive physiology were accompanied by a significant decrease in neonatal sex steroid levels and suppression of the plasma concentrations of testosterone (male) and estradiol (female) during puberty. In male pups, this was accompanied by a significant decrease in plasma luteinizing hormone (LH), elevated pituitary LH content, and a decrease in plasma testosterone/LH ratios at the highest dose. In female pups, although no effects were observed on plasma LH concentration, a similar significant elevation in pituitary LH content was observed during early puberty. Postpuberty, plasma LH and sex steroid concentrations were unaffected at any dose in spite of continued lead exposure. No significant effects were observed on epididymal sperm count in male pups at 85 d of age. In female pups, estrus cycling was only significantly disrupted at the highest lead dose. These data suggest that the reproductive axis is particularly sensitive to lead during specific developmental periods, resulting in delayed sexual maturation produced by suppression by sex steroid biosynthesis. The mechanisms underlying this appear to involve lead actions on both LH release and gonadal function. At low, environmentally relevant blood lead concentrations, adaptation to the continuous presence of the metal ion occurs and surprisingly little effect is observed on adult reproductive endocrinology and physiology.     

Developmental and behavioral effects of prenatal primidone exposure in the rat

Pregnant Sprague-Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight-arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM-treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system.     

Patterns of ovarian growth and development in cattle with a growth hormone receptor deficiency

Nutritionally induced changes in growth hormone (GH) and IGF-I are associated with decreased ovarian function and may partially explain infertility and anestrus in undernourished cattle. The reproductive importance of GH and IGF-I was tested in cattle with a GH receptor deficiency (GHRD) that have reduced blood IGF-I. Blood was collected daily for plasma, and ovaries were examined daily by ultrasonography for 3 wk during an estrous cycle (estrus = d 0) in GHRD (n = 8) and control (n = 8) cattle. On d 18, blood samples were collected every 10 min for 6 h to measure LH. The GHRD cattle had fewer small antral ovarian follicles (2 to 5 mm, P < .01). After estrous cycle d 5, the first-wave dominant follicle stopped growing in GHRD but continued growing in controls (P < .001). Size of the CL was equivalent for GHRD and controls until d 5, after which CL development slowed in GHRD (P < .01). Likewise, plasma progesterone concentrations were less in GHRD (P < .001). During the luteal phase, GHRD cattle failed to develop follicles greater than 10 mm in diameter (endocrine status x day, P < .05). Size and rate of growth of preovulatory follicles, plasma estradiol, plasma FSH, and plasma LH (d 18 bleed) were similar in GHRD and controls. In conclusion, an important role for GH, GH receptor, and IGF-I in ovarian function was supported because GHRD cattle had distinctly different patterns of ovarian development compared with control cattle.     

Serum steroid hormones and the reproductive cycle of the female bonnethead shark, Sphyrna tiburo

The bonnethead shark Sphyrna tiburo reproduces by placental viviparity with one of the shortest gestation periods (4.5-5 months) known in sharks. In southwest Florida, mating in this species occurs in November, sperm is stored until ovulation/fertilization the following March-April, and parturition occurs in August. Serum concentrations of four steroid hormones (17 beta-estradiol, progesterone, testosterone, and dihydrotestosterone) were determined by radioimmunoassay over a complete reproductive cycle in mature females from a wild population. Serum 17 beta-estradiol and testosterone levels are high during mating and preovulatory stages. Preovulatory concentrations of testosterone are greater in female S. tiburo than in any other female elasmobranch previously studied. Progesterone levels are significantly elevated during preovulatory, ovulatory, and postovulatory stages, while serum dihydrotestosterone levels increase significantly during the preovulatory stage. Our study is the first to demonstrate a sustained rise in progesterone during gestation in a placental shark and suggests a regulatory role for this hormone during the period prior to implantation of the embryos in the uterus.     

Combined oral contraceptives and gonadotropin releasing hormone agonistic analogs in polycystic ovary syndrome: clinical and experimental studies

Polycystic ovary syndrome is a common endocrine disorder, presenting with menstrual irregularities, hirsutism, obesity, infertility and abnormal ovarian morphology. In addition, polycystic ovary syndrome is associated with a self-perpetuating imbalance involving the endocrine system and metabolic pathways, in which carbohydrates, lipids and growth factors are involved. Because of its chronicity, it is considered to be a substantial risk factor for atherogenesis and hormone-dependent neoplasia. The etiology and pathophysiology of the syndrome remain elusive. However, during the last decade, several clues have emerged from human and animal studies that may have significant repercussions in the treatment of polycystic ovary syndrome. Therapeutic maneuvers should be directed towards the dominant abnormalities present in individual patients with polycystic ovary syndrome. Gonadotropin releasing hormone (GnRH) agonists can directly affect the gonadotropin generator and secondary downstream derangements, whereas combined oral contraceptives (COCs) can modify hypothalamic as well as peripheral abnormalities. In view of the fact that GnRH agonistic analogs (GnRH-a) will induce hypoestrogenemia and its sequelae, the add-back strategy of estrogenic supplementation is recommended for preventive reasons and, as it transpires from some studies, for enhancement of GnRH-a effectiveness.     

The ovarian renin-angiotensin system in reproductive physiology

The identification of the presence of prorenin, renin, angiotensinogen, angiotensin-converting enzyme, angiotensin II (Ang II), and Ang II receptors in the ovary suggests that there is a functional ovarian renin-angiotensin system (RAS). It could play a significant role in such areas of ovarian physiology as follicular development, steroidogenesis, oocyte maturation, ovulation, and follicle atresia. Expression of the ovarian RAS is regulated by gonadotropins. Ang II, a bioactive octapeptide of RAS, has important effects as a paracrine/autocrine regulator at different stages of the reproductive cycle. Ang II modulates ovarian steroidogenesis and formation of the corpus luteum and also stimulates oocyte maturation and ovulation via Ang II receptors on granulosa cells. In addition, increasing evidence demonstrates that Ang II is a major factor in regulating the function of atretic follicles. In any physiologic system, aberrations result in the development of pathologic states. Disturbances in the ovarian RAS can be the cause or the result of such reproductive disorders as polycystic ovary syndrome, ovarian hyperstimulation syndrome, ovarian tumors, and ectopic pregnancy. Data support the concept of an active and regulated RAS in ovarian follicles. Species differences observed in the expression of ovarian RAS suggest varying functional roles among species with respect to ovarian physiology.     

Two cases of true hermaphrodite: the usefulness of laparoscopic gonadectomy in childhood. A case report

Laparoscopic operation has been an alternative method in not only adults but children. We presented two children with true hermaphroditism who were performed by open gonadectomy and laparoscopic gonadectomy respectively. Both patients at the age of 4, and 2 years showed karyotypes of 46, XX, and were raised as girls. In the first case left ovary and right ovotestis were revealed by open gonadal biopsy and right ovotestis was removed by open surgery. In another case bilateral ovotestes were revealed by laparoscopic gonadal biopsy and resected by laparoscopic procedure. Laparoscopy was very useful for detecting the gonadal structures to confirm the diagnosis in intersex patients. True hermaphrodite is one of uncommon intersex anomalies, therefore the diagnosis should be made to demonstrate the coexistence of both ovarian and testicular tissues definitely. We estimated laparoscopic gonadectomy in pediatric true hermaphrodite and concluded that laparoscopic gonadectomy was as profitable as open gonadectomy.     

Current trends in modern orthokeratology

This article reviews current knowledge on the effect of testicular germ cell cancer (TGCC) on gonadal function and of the cancer treatment on spermatogenesis and Leydig cell function. It seems likely that development of TGCC shares common etiological factors with development other types of testicular dysfunction. This suggestion is supported by the observation that men with various types of gonadal dysfunction such as testicular dysgenesis, androgen insensitivity syndrome, and cryptorchidism have increased risk of testicular cancer. Epidemiological and clinical data indicate common etiology between testicular germ cell cancer and other abnormalities in male reproductive health such as infertility and cryptorchidism. These observations are in agreement with the suggestions of hormonal involvement in the etiology of testicular cancer. It is well documented that testicular cancer is associated with impaired spermatogenic function and some patients have impairment of Leydig's cell function already before orchidectomy. The degree of spermatogenic dysfunction is higher than what can be explained by local tumor effect and by a general cancer effect. These observations are supported by histological investigations, which have shown a high prevalence of abnormalities of spermatogenesis in the contralateral testis in patients with unilateral TGCC. The spermatogenetic function is still severely impaired after orchidectomy and radiotherapy as well as chemotherapy induce further dose-dependent impairment of spermatogenesis. Recovery of spermatogenesis after treatment may be long, in some patients lasting more than 5 years. Sufficient androgen production is seen in the majority of the patients but some patients do suffer from testosterone deficiency. The effect of chemotherapy on Leydig's cell function seems to be dose dependent. Trials on protection of spermatogenetic function against the harmful effects of radiotherapy and chemotherapy by suppression of spermatogenesis has not been successful. The only way to maintain fertility is to limit gonadal exposure to harmful agents. Moreover cryopreservation of semen should be done before treatment. The optimal time for cryopreservation is before orchiectomy at least in some patients. Generally men with TGCC need counselling about their reproductive function, with respect to semen cryopreservation, chance for recovery of spermatogenesis, fertility, and the possibility of need for androgen replacement.     

Quality assurance in dentistry: the Dutch approach

We reviewed gonadal function in 270 patients who underwent bone marrow transplantation (BMT) between 1974 and 1988. Age at transplant ranged from 6 to 54 years (mean 25.6 years). Diagnoses included acute myelogenous leukemia, chronic myelogenous leukemia, aplastic anemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin's disease and other diagnoses. Effects of patient characteristics on risk of gonadal dysfunction were analyzed by comparing the cumulative probability of developing gonadal dysfunction over time from BMT. Ninety-two percent of the males and 99% of the females developed evidence of gonadal dysfunction. Females were not only more likely to develop elevated gonadotrophin levels than males, but did so earlier after BMT. Odds ratios were calculated to determine potentially important prognostic factors for the development of an elevated gonadotrophin level. Older age at BMT was correlated with an increased risk in the development of elevated gonadotrophin levels. Individuals who received radiation were more likely to develop an elevated FSH level over time than those who had received no preparative radiation treatment. Males were more likely to experience gonadal recovery than females. In those cases that did recover, males tended to recover more quickly after BMT than females.     

Endocrine disruption in wildlife: a critical review of the evidence

In recent years, a number of man-made chemicals have been shown to be able to mimic endogenous hormones, and it has been hypothesized that alterations in the normal pattern of reproductive development seen in some populations of wildlife are linked with exposure to these chemicals. Of particular importance are those compounds that mimic estrogens and androgens (and their antagonists), because of their central role in reproductive function. In fact, the evidence showing that such chemicals actually do mimic (or antagonize) the action of hormones in the intact animal is limited. In only a few cases have laboratory studies shown that chemicals that mimic hormones at the molecular level (in vitro) also cause reproductive dysfunction in vivo at environmentally relevant concentrations. In addition, the reported studies on wild populations of animals are limited to a very few animal species and they have often centered on localized 'hot-spots' of chemical discharges. Nevertheless, many of these xenobiotics are persistent and accumulate in the environment, and therefore a more widespread phenomenon of endocrine disruption in wildlife is possible. This article reviews the evidence, from both laboratory and field studies, that exposure to steroid hormone mimics may impair reproductive function and critically assesses the weight of evidence for endocrine disruption in wildlife.     

Ovarian abscess following puncture of an endometrioma during ultrasound-guided oocyte retrieval

A 34-year-old white female patient with 11 years of primary infertility due to endometriosis underwent ultrasound-guided oocyte retrieval for in-vitro fertilization. A right ovarian endometrioma was aspirated during oocyte retrieval. Two weeks after follicular aspiration, the patient developed acute abdominal pain and operative laparoscopy revealed a ruptured right ovarian abscess. She responded to laparoscopic drainage and intravenous antibiotics. The patient conceived during that cycle and has a single ongoing pregnancy.     

Solution of methodological problems in prorenin measurement and investigations of tissue renin-angiotensin systems in the female reproductive tract

The literature has been provided with conflicting results concerning prorenin in rat plasma. The cause was investigated and we characterized severe methodological problems. Prorenin is in rats measured by its enzymatic property after trypsin activation. Besides activating prorenin, trypsin appeared to degrade renin substrate (angiotensinogen) and formed an unstable 'blank' which interfered in the prorenin measurement. An interfering sulphydryl enzyme was also found in plasma from nephrectomized rats. Identical 'blank' problems were also found in other animals such as pigs and cattle. These problems were solved and a new validated method was developed enabling the study of active renin and prorenin in species other than humans. Plasma prorenin was found primarily to originate from kidneys in rats as in other species although minor contribution of other tissues was likely. Evidence has accumulated during recent years supporting the existence of local tissue RAS's in ovary and uteroplacental unit. The presence of active renin and prorenin in female reproductive organs were verified in cattle and pigs. A marked species difference was found. Secretion of prorenin to plasma only seemed to take place in humans suggesting primarily a local function of reproductive RAS's. The concentration of prorenin varies during follicular maturation and pregnancy in reproductive tissues and fluids. A tissue incubation method was developed to study the bovine ovarian RAS in-vitro. The presence, formation, secretion and degradation of active renin in bovine ovarian follicles in-vitro indicate that active renin--and not prorenin as suggested earlier--is important in mediating effects of tissue RAS. Angiotensin II receptors are also present in high and varying densities in the ovary, uterus and placenta. Several potential effects, mediated through auto- or paracrine actions, are suggested. Ovarian RAS may affect oocyte maturation, ovulation, steroidogenesis and angiogenesis. The uteroplacental RAS may affect decidualization, angiogenesis, hormone synthesis, local blood flow and uterine contraction. Effects may, according to the marked species difference of RAS, vary between species. The understanding of tissue RAS's is in its infancy. The ovary seems to be a very good model in study of tissue RAS's and their possible relations to the bloodborne RAS. Further investigation may also benefit the reproductive endocrinology.     

Gonadal function in men with testicular cancer: biological and clinical aspects

This paper reviews current knowledge about the effect of testicular germ cell cancer (TGCC) on gonadal function and of cancer treatment on spermatogenesis and Leydig cell function. It is well documented that testicular cancer is associated with impaired spermatogenic function and some patients already have impairment of Leydig cell function before orchidectomy. The degree of spermatogenic dysfunction is higher than what can be explained by local tumour effect and by a general cancer effect, since patients with other malignant diseases have normal, or only slightly decreased, semen quality. Furthermore, sperm counts after orchidectomy are further reduced to less than half of the values in healthy men, even in patients cured from the cancer disease after orchidectomy alone. These observations are supported by histological investigations which have shown a high prevalence of abnormalities of spermatogenesis in the contralateral testis in patients with unilateral TGCC. The association between testicular cancer and poor gonadal function is very interesting both from a biological and from a therapeutic point of view. Firstly, the increase in incidence of testicular cancer has been suggested to be associated with a general decline in male reproductive health and it seems likely that the development of TGCC shares common aetiologic factors with development of other types of testicular dysfunction. This suggestion is supported by the observation that men with various types of gonadal dysfunction such as testicular dysgenesis, androgen insensitivity syndrome, and cryptorchidism have increased risk of testicular cancer. Secondly, the general cure rate in patients with testicular cancer exceeds 90% and the quality of life, including fertility aspects, is therefore important in the management of these patients. Spermatogenesis is already so severely impaired before treatment that fertility is lower than in healthy men. Moreover, radiotherapy and chemotherapy both induce dose-dependent impairment of spermatogenesis and recovery of spermatogenesis after treatment may be long lasting even more than five years in some patients. Sufficient androgen production is seen in the majority of the patients, but some patients suffer from testosterone deficiency. The effect of chemotherapy on Leydig cell function also seems to be dose-dependent. In conclusion there is no doubt that testicular cancer is associated with poor gonadal function even before treatment. Furthermore, the treatment of testicular cancer may have a serious impact on the gonadal function in these patients, most of whom are in the reproductive age. Moreover, the epidemiological and clinical data indicate a common aetiology between testicular germ cell cancer and other abnormalities in male reproductive health (such as infertility and cryptorchidism). These observations are in agreement with the suggestions of hormonal involvement in the aetiology of testicular cancer. Generally, men with TGCC need counselling about their reproductive function with respect to semen cryopreservation, chance of recovery of spermatogenesis, fertility, and the possible need for androgen replacement.