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PubMed1988

Promotion of research in human reproduction: global needs and perspectives.

The WHO Special Programme of Research, Development and Research Training in Human Reproduction was established in 1972, to respond to a global expansion in research needs in human reproduction, especially in the area of fertility regulation. The Programme's limited resources come from voluntary contributions by governments and international agencies. The emphasis is always on the needs of developing countries. The Programme has to keep the field under continuous review, and to direct its limited resources to the major unmet needs. This paper presents, from a global perspective, the needs and priorities in the promotion of research in human reproduction. It is emphasized that research has to be backed up by political commitment and resources if it is to have an impact on reproductive health. The role of determinants of health, other than and beyond the medical services, has also to be recognized. Promotion of research in human reproduction, to serve developing country needs, has to move into two directions. One is the mobilization of a global effort to develop and test technologies, where the available technologies are not satisfactory to meet the needs and where the research is slackening. The second is the strengthening of in-country resources for research to deal with country-specific problems and to enable countries to utilize, to the best, available technologies.

Contraception↗
PubMed2002

Assessment of reproductive function in mutant restricted ovulator carrier roosters.

Two splice variant forms of the chicken very low density lipoprotein receptor (VLDLR) have recently been shown to exist in both male and female chicken gonads. The longer form, containing an O-linked sugar domain, is produced in the somatic cells of the testes and ovaries, whereas the shorter form, which lacks this domain, is expressed in the male and female germ cells. The latter is essential for female reproduction, because a naturally occurring point mutation in the gene encoding the short form of the VLDLR causes its functional absence, resulting in atherosclerosis and a general failure to lay eggs. Thus, the term restricted ovulator (RO) was originally coined to describe females with the mutant gene. In contrast, the roles of the VLDLR gene products in male reproduction have yet to be defined, because only heterozygous RO roosters, which have a mutant allele of the VLDLR gene (short form) on one of their two Z (sex) chromosomes, can be obtained. However, the question of whether two normal alleles of the VLDLR gene are needed for optimal male reproductive performance can be addressed. Here, the reproductive abilities of heterozygous RO roosters were compared to their wild-type siblings. The RO roosters were found to be phenotypically normal, suggesting that only one normal allele for the VLDLR gene is needed for optimal male reproductive performance. Alternately, it is also possible that the one normal allele compensated for the presence of the mutant one in terms of VLDLR gene product production (i.e., a dosage compensation).

Alternative Splicing↗
PubMed2003

Nuclear receptor coactivator function in reproductive physiology and behavior.

Gonadal steroid hormones act throughout the body to elicit changes in gene expression that result in profound effects on reproductive physiology and behavior. Steroid hormones exert many of these effects by binding to their respective intracellular receptors, which are members of a nuclear receptor superfamily of transcriptional activators. A variety of in vitro studies indicate that nuclear receptor coactivators are required for efficient transcriptional activity of steroid receptors. Many of these coactivators are found in a variety of steroid hormone-responsive reproductive tissues, including the reproductive tract, mammary gland, and brain. While many nuclear receptor coactivators have been investigated in vitro, we are only now beginning to understand their function in reproductive physiology and behavior. In this review, we discuss the general mechanisms of action of nuclear receptor coactivators in steroid-dependent gene transcription. We then review some recent and exciting findings on the function of nuclear receptor coactivators in steroid-dependent brain development and reproductive physiology and behavior.

Animals↗
PubMed2004

Prenatal programming of reproductive neuroendocrine function: the effect of prenatal androgens on the development of estrogen positive feedback and ovarian cycles in the ewe.

Exposure of the female ovine fetus to male hormones during a sensitive window of in utero life causes disruption to reproductive function. In some animals, androgen exposure completely abolishes reproductive cycles, but in others, cycles are progressively lost with age. The present study tested two predictions: that noncycling, androgenized animals are unable to respond to estrogen with a preovulatory-like surge of LH (estrogen positive feedback), and that the androgenized animals that exhibit a progressive loss of cycles also show a progressive loss of estrogen positive feedback. Androgenized ewes were generated by injection of their mothers with testosterone propionate twice per week from Day 30 to Day 90 of pregnancy (term, 147 days). Control ewes received no injections. Whether ewes could exhibit estrogen positive feedback was tested on five occasions before puberty (30 wk) and once during the anestrous period. All control animals had repeated reproductive cycles in both the first and second breeding season, and all showed robust LH surges during test periods. Despite the fact that 64% of androgenized animals showed reproductive cycles, estrogen positive feedback could be demonstrated in only 6.1% of trials. Subsequent experiments revealed that the lack of response to estrogen in androgenized animals was not because of pituitary insensitivity to GnRH, a requirement for higher concentrations of estrogen, or a surge that was delayed relative to the time of estrogen administration. The mechanisms by which some androgenized ewes can produce normal reproductive cycles in the apparent absence of estrogen positive feedback are currently unknown.

Animals↗
PubMed1982

Photoperiod and reproduction in female deer mice.

Female deer mice were exposed to a short day (SD, 6L:18D) photoperiod beginning during 1 of 3 stages of life. In the first experiment, exposure to SD during adulthood resulted in a minimal disruption of reproductive condition; many females bore 2 litters after the onset of this treatment. In the second experiment, females reared on SD from weaning matured normally, as measured by vaginal introitus; however, vaginal closure occurred in approximately one-half of these females by 9 weeks of age. In the third experiment, females were born of mothers housed on either an SD or a long day photoperiod, and were continued on the maternal photoperiod until 6 weeks of postnatal age. The SD photoperiod markedly inhibited reproductive maturation as measured by vaginal patency, ovarian weight, and uterine weight. A comparison of reproductive organ weights and vaginal condition provided evidence for the validity of the latter measure as an index of reproductive state. As assayed by the present testing procedure, the sensitivity of the reproductive system to photoperiod decreases as a function of age in female deer mice.

Animals↗
PubMed1986

Assessment of reproductive risks.

In the regulatory process, the hazards posed by potentially toxic agents to the female and male reproductive systems and to developing young are evaluated by risk assessment procedures. In this paper, toxicity testing and the regulatory process are discussed, with emphasis on risk assessment. The suggested testing protocols of the Pesticide Assessment Guidelines (U.S. EPA) are presented as an example of testing that might be done to produce toxicity data for an agent. Protocols and end points that are utilized in testing for reproductive effects are described. Included are acute, subchronic, chronic, and short-term tests. The four components of reproductive risk assessment (hazard identification, dose-response assessment, exposure assessment, and risk characterization) are examined. Effects of dibromochloropropane on rabbit testicular parameters are used to demonstrate approaches that could be taken in doing a reproductive risk assessment. Research needs for screening methods, adequate dose-response testing, toxicokinetics, end point development, and extrapolation methods are identified. Finally, this paper discusses selected areas in which changes in reproductive risk assessment are anticipated, as well as the mechanism for influencing the nature and extent of those changes.

Abortion, Spontaneous↗
PubMed1994

Photoperiodic synchronization of a circannual reproductive rhythm in sheep: identification of season-specific time cues.

Seasonal reproduction in the ewe is generated by an endogenous circannual rhythm of reproductive neuroendocrine activity. Exposure to as few as 70 days of photoperiodic information a year is sufficient to synchronize the rhythm. The present study was conducted to identify which portions of the photoperiodic cycle are utilized for synchronization. For this purpose, we used pinealectomized ewes that could not respond reproductively to changes in day length. Selected photoperiodic information was provided via infusion of melatonin, a hormone that provides the neuroendocrine code for day length in this species. Melatonin was delivered according to circadian patterns. The infusion patterns were tailored to mimic those of melatonin secretion in pineal-intact ewes during one of the four seasons: winter, spring, summer, or autumn. The infusions were provided for 90 days a year during each of the three years following pinealectomy. The ewes were ovariectomized and treated with constant-release Silastic capsules containing estradiol; reproductive neuroendocrine activity was monitored by measurement of serum concentrations of LH. In the absence of exogenous melatonin, most (19 of 24) pinealectomized controls exhibited circannual LH cycles that were not in synchrony, indicating that the rhythm was free-running. Melatonin synchronized the rhythm (such that the period was 365 days and the stages of the rhythm were both concurrent among animals and in appropriate phase with the geophysical year), but not all melatonin patterns were equally effective in this regard. The most effective melatonin patterns mimicked those of secretion during summer. Spring and autumn melatonin patterns were less effective, and winter melatonin patterns were ineffective. These results support the concept that there is a seasonal specificity with regard to the photoperiodic cues that synchronize the circannual rhythm of reproductive neuroendocrine activity in the ewe. The rhythm is synchronized most effectively by long-day photoperiodic cues perceived on or around the summer solstice.

Animals↗
PubMed1996

Chemical cues are necessary but insufficient for reproductive activation of female pine vole (Microtus pinetorum).

Among various arvicoline rodents, reproduction is influenced to varying degrees by social factors, including behavioral or chemical cues. Since previous research suggested that chemosignals from adult males reproductively activate female pine voles (Microtus pine-torum), we sought to determine specifically what types of stimuli promote the activation response. In these experiments, female were exposed to unfamiliar adult males, or to some combination of cues from males, or were housed alone. Using uterine mass as a measure of reproductive activation, we found that females were not activated by exposure either to male urine by itself or to male-soiled bedding by itself, but full contact with a male clearly resulted in heavier uteri. Females whose vomeronasal organs were surgically excised failed to undergo reproductive activation when housed with males. Finally, females allowed physical contact by being housed directly underneath males had heavier uteri than did females whose housing allowed contact only with the chemical cues from males. Among female arvicoline rodents, it appears that there exists a physiological continuum between absolute dependence on both contact and chemical cues from males vs. absolute independence for reproductive activation. The present results place female pine voles closer to the former extreme than to the latter.

Animals↗
PubMed1998

Effects of neonatal administration of diethylstilbestrol in male hamsters: disruption of reproductive function in adults after apparently normal pubertal development.

Prenatal and neonatal exposure to natural and synthetic estrogens induces developmental abnormalities in the male and female reproductive systems in several species. In hamsters, a single injection of diethylstilbestrol (DES) on the day of birth induces teratogenic and neoplastic changes throughout the female reproductive tract, apparently via a direct mechanism. The present study investigated the extent and specificity of this phenomenon in the male reproductive system. Male golden hamsters received injections of DES or estradiol-17beta (E2; 100 microg/ animal) on the day of birth and were then killed at 42 (pubertal) and 90 (adults) days of age. Blood was collected for serum testosterone analysis, and the testes and accessory organs were weighed and examined histologically. At the pubertal stage, testicular and accessory organ weights plus serum testosterone levels were similar in untreated animals and in both groups of estrogen-treated animals. Also at the pubertal stage, initiation of spermatogenesis appeared normal in both groups of estrogen-treated animals. In contrast, 100% of the DES-treated animals (n = 22) but none of the E2-treated animals exhibited multiple lesions in the reproductive tract as adults. These DES-induced lesions included cryptorchidism with the testes attached to the abdominal wall, solid testicular tumors, multiple epididymal cysts, and involution of accessory organs. Spermatogenesis was disrupted in the seminiferous tubules, with no developing germ cells, and the interstitial cells were organized as a sheath around the dysfunctional tubules. The epididymis had an involuted epithelial layer with a preponderance of multi-nucleated cells, and seminal vesicle morphology was also abnormal. These DES-specific alterations were not accompanied by any significant change in circulating testosterone levels. We therefore conclude that 1) DES is much more potent that E2 as a neonatal endocrine disrupter in the male hamster, and 2) the DES-specific lesions in the adult male reproductive tract may represent a permanently altered androgen responsiveness in the affected target tissues.

Animals↗
PubMed2000

Importance of photoperiodic signal quality to entrainment of the circannual reproductive rhythm of the ewe.

An endogenous circannual rhythm drives the seasonal reproductive cycle of a broad spectrum of species. This rhythm is synchronized to the seasons (i.e., entrained) by photoperiod, which acts by regulating the circadian pattern of melatonin secretion from the pineal gland. Prior work has revealed that melatonin patterns secreted in spring/summer entrain the circannual rhythm of reproductive neuroendocrine activity in sheep, whereas secretions in winter do not. The goal of this study was to determine if inability of the winter-melatonin pattern to entrain the rhythm is due to the specific melatonin pattern secreted in winter or to the stage of the circannual rhythm at that time of year. Either a summer- or a winter-melatonin pattern was infused for 70 days into pinealectomized ewes, centered around the summer solstice, when an effective stimulus readily entrains the rhythm. The ewes were ovariectomized and treated with constant-release estradiol implants, and circannual cycles of reproductive neuroendocrine activity were monitored by serum LH concentrations. Only the summer-melatonin pattern entrained the circannual reproductive rhythm. The inability of the winter pattern to do so indicates that the mere presence of a circadian melatonin pattern, in itself, is insufficient for entrainment. Rather, the characteristics of the melatonin pattern, in particular a pattern that mimics the photoperiodic signals of summer, determines entrainment of the circannual rhythm of reproductive neuroendocrine activity in the ewe.

Animals↗
PubMed1985

Fertility, reproduction, and postnatal survival in mice chronically exposed to isoflurane.

The effects on fertility and reproductive wastage of 110 female Swiss/Webster mice and postnatal survival of their offspring were examined after exposure to either air, 0.4% isoflurane, or 0.1% isoflurane. Treatments were for 4 h daily for 2 weeks before and during pregnancy. In a second experiment, the effects on fertility of 54 male Swiss/Webster mice and on reproductive wastage of their unexposed mates were examined after 4-h daily exposures to either air, 0.4% isoflurane, or 0.1% isoflurane throughout spermatogenesis and during mating. There were no adverse reproductive effects in either experiment. The lack of toxicity of isoflurane is consistent with the results of other reproductive studies in animals that have examined chronic intermittent exposure to subanesthetic concentrations of halothane, enflurane, methoxyflurane, and nitrous oxide. They suggest that these and lower (trace) levels of anesthetic gases may not be the cause of the harmful reproductive effects said to occur in operating room personnel.

Anesthesia, Inhalation↗
PubMed1997

Reproductive disorders among hairdressers.

To evaluate whether hairdressers have an increased risk of reproductive disorders, we conducted a historical cohort study in the Netherlands. Because exposure to reproduction toxic agents in hair salons may have changed over time, we studied two specific periods: conceptions in 1986-1988 and in 1991-1993. We ascertained 9,000 hairdressers and, as a comparison group, 9,000 clothing salesclerks from their respective trade associations. All were of reproductive age in the defined study periods. Frequency matching on 5-year age groups ensured comparability with regard to age. All women were approached by mail to complete a short, self-administered questionnaire on reproductive history, including questions on time-to-pregnancy, spontaneous abortion, livebirths, and congenital malformations. In the analyses, we used random effect models to account for correlated outcomes (multiple pregnancies per woman). The results show that hairdressers who conceived in 1986-1988 had an increased risk of prolonged time-to-pregnancy of more than 12 months [odds ratio (OR) = 1.5; 95% confidence interval (CI) = 0.8-1.6], spontaneous abortion (OR = 1.6; 95% CI = 1.0-2.4), and a low-birthweight infant (OR = 1.5; 95% CI = 0.7-3.1). In both periods, more major malformations occurred among children of hairdressers, but numbers were small. These results indicate an increase in reproductive risks for hairdressers in earlier years that now seems to be disappearing.

Abnormalities, Drug-Induced↗
PubMed2000

Gynecological and reproductive issues for women in space: a review.

Women have been an integral part of United States space crews since the initial flight of Dr. Sally Ride in 1983, and a total of 40 women have been selected as U.S. astronauts. This article examines the reproductive and gynecological aspects of selecting, training, medically certifying, and flying women in space. Gynecological data from the astronaut selection cycles in 1991 to 1997 are reviewed. In addition, the reproductive implications of delaying childbearing for a career as an astronaut and the impact of new technology such as assisted reproductive techniques are examined. The reproductive outcomes of U.S. female astronauts after spaceflight are also presented. Because women have gained considerable operational experience on the Shuttle and Mir, the unique operational considerations for preflight certification, menstruation control and hygiene, contraception, and urination are discussed. Medical and surgical implications for women on long-duration missions to remote locations are still evolving, and enabling technologies for health care delivery are being developed. There has been considerable progress in the development of zero-gravity surgical techniques, including laparoscopy, thoracoscopy, and laparotomy. The concepts of prevention of illness, conversion of surgical conditions to medically treatable conditions, and surgical intervention for long-duration spaceflights are explored in detail. There currently are no operational gynecological or reproductive constraints for women that would preclude their successful participation in the exploration of our nearby solar system.

Adult↗
PubMed2005

Urinary phthalate metabolites and biomarkers of reproductive function in young men.

BACKGROUND: High exposure to phthalates, which are ubiquitous contaminants, has been shown in animal studies to produce detrimental effects on male reproductive functions. A recent study in humans reported dose-response relations between low phthalate levels in urine and human semen parameters, which raises the question whether humans are more sensitive to phthalate exposure than animals. METHODS: Urine, serum, and semen samples were collected from 234 young Swedish men at the time of their medical conscript examination. Semen volume, sperm concentration, and motility were measured, together with sperm chromatin integrity (sperm chromatin structure assay) and biochemical markers of epididymal and prostatic function. We analyzed reproductive hormones in serum, and mono ethyl phthalate (MEP), mono ethylhexyl phthaltale (MEHP), mono benzyl phthalate (MBzP), mono butyl phthalate (MBP), and phthalic acid in urine. RESULTS: For MBP, MBzP, and MEHP, no clear pattern of associations were observed with any of the reproductive biomarkers. Subjects within the highest quartile for MEP had fewer motile sperm (mean difference = 8.8%; 95% confidence interval = 0.8-17), more immotile sperms (8.9%; 0.3-18), and lower luteinizing hormone values (0.7 IU/L; 0.1-1.2), but there was no suggestion of harmful effects for most other endpoints. Phthalic acid actually was associated with improved function, as measured by several markers. CONCLUSIONS: The observed weak associations between 1 phthalate biomarker and impairment of a few aspects of reproductive function biomarkers were not consistent with results from a recent U.S. study. It is not yet possible to conclude whether phthalate exposure may reflect a hazard for human male reproduction.

Adolescent↗
PubMed2006

Imprinting disorders after assisted reproductive technologies.

PURPOSE OF REVIEW: To assess the evidence of an increased risk of imprinting diseases in children born after use of assisted reproductive technologies. RECENT FINDINGS: Imprinting disorders occur when the epigenetic programming during gametogenesis is disturbed, or when this programming is not sufficiently sustained during the process of fertilization and early embryonic development. Ten case or case-reference reports have been published suggesting that compared with reference populations, a higher proportion of children with imprinting diseases were conceived by assisted reproductive technologies. These reports are inconsistent in linking the risk to a specific assisted reproductive technology, and a cytogenetic examination assessing the exact genetic imprinting mechanism was not always provided. Two national systematic follow-up studies on 6052 Danish and 16,280 Swedish in-vitro fertilization children found none and two children with imprinting diseases, respectively. These figures correspond approximately to the expected number of children with imprinting disease from the general population. SUMMARY: The evidence of an increased risk of imprinting diseases in children conceived by assisted reproductive technologies is limited. The published case reports, however, call for a systematic multinational long-term follow-up of children born after assisted reproductive technologies.

Animals↗
PubMed2006

Immune challenge retards seasonal reproductive regression in rodents: evidence for terminal investment.

Animals must balance investments in different physiological activities to allow them to maximize fitness in the environments they inhabit. These adjustments among reproduction, growth and survival are mandated because of the competing high costs of each process. Seasonally breeding rodents generally bias their investments towards reproduction when environmental conditions are benign, but shift these investments towards processes that promote survival, including immune activity, when environmental conditions deteriorate. Because survival probability of non-tropical small mammals is generally low in winter, under certain circumstances, these animals may not allocate resources to survival mechanisms in an effort to produce as many offspring as possible in the face of increased probability of death. Such 'terminal investments' have been described in passerines, but there are few examples of such phenomena in small mammals. Here, we show that male Siberian hamsters (Phodopus sungorus) challenged with lipopolysaccharide (a component of gram-negative bacteria that activates the immune system) induced a small, but significant, retardation of seasonal regression of the reproductive system relative to saline-injected hamsters. This delayed reproductive regression likely reflects a strategy to maintain reproductive function when survival prospects are compromised by infection.

Acclimatization↗
PubMed1980

Reduced reproductive performance in androgen-resistant Tfm/Tfm female mice.

Androgen-resistant female mice (Tfm/Tfm) homozygous for the mutant gene Tfm were bred by making use of males chimaeric for the Tfm gene. All seven Tfm/Tfm females found were fertile, confirming that a normal level of androgen receptor protein is not essential for reproduction in female mice. However, when five of the seven were studied throughout their reproductive life they proved to have impaired reproductive performance and premature cessation of reproduction. No impairment of reproduction was seen in heterozygous Tfm/+ females. The ovarian histology suggested that in Tfm/Tfm the normal ageing processes were accelerated. This work is consistent with the work of others in that androgen is involved in the control of follicular maturation and atresia, and that the effect is mediated by the androgen receptor coded by the Tfm locus.

Androgens↗
PubMed1998

Sexual reproduction and population dynamics: the role of polygyny and demographic sex differences.

Most models of population dynamics do not take sexual reproduction into account (i.e., they do not consider the role of males). However, assumptions behind this practice--that no demographic sex differences exist and males are always abundant enough to fertilize all the females--are usually not justified in natural populations. On the contrary, demographic sex differences are common, especially in polygynous species. Previous models that consider sexual reproduction report a stabilizing effect through mixing of different genotypes, thus suggesting a decrease in the propensity for complex of dynamics in sexually reproducing populations. Here we show that considering the direct role of males in reproduction and density dependence leads to the conclusion that a two-sex model is not necessarily more stable compared with the corresponding one-sex model. Although solutions exist where sexual reproduction has a stabilizing effect even when no genotypic variability is included (primarily when associated with monogamy), factors like polygyny, sex differences in survival or density dependence, and possible alterations of the primary sex ratio (the Trivers-Willard mechanism), may enlarge the parametric region of complex dynamics. Sexual reproduction therefore does not necessarily increase the stability of population dynamics and can have destabilizing effects, at least in species with complicated mating systems and sexual dimorphism.

Animals↗