Vaccines for control of fertility.

Major developments in birth control vaccines are on the horizon. The human chorionic gonadotropin (hCG) vaccine has entered phase II clinical trials after successful completion of phase I studies at 5 centers in India and 4 centers abroad. It is the most advanced vaccine of its type in the world. The trials are being conducted on women of proven fertility who are sexually active. The available results indicate the efficiency of the vaccine to prevent pregnancy in women at or above titres of 50 ng/ml. A vaccine inducing antibodies against gonadotropin releasing hormone (GnRH) has been approved in India for trials in postpartum women, to determine whether immunization can help prolong lactational amenorrhea. The GnRH vaccine is also in clinical trial in prostate cancer patients at 2 centers in India and in Austria and the Dominican Republic. The follicle stimulating hormone (FSH) vaccine is about to enter phase I clinical trial after completing experimental and toxicological studies. A vaccine against FSH has been developed for human males employing ovine FSH (oFSH) as an immunogen. oFSH adsorbed on alum induces antibodies reactive with human FSH in bonnet monkeys. Immunization leads to oligospermia with resultant impairment of fertilization potential. No reduction in testosterone levels has been reported. Research is in progress to identify antigens on spermatozoa, which could serve as vaccine candidates. PH-20, a protein located on the inner acrosomal membrane of capacitated sperms, has been reported to have 100% contraceptive efficacy in both sexes of guinea pigs in active immunization studies. cDNA probes of PH-20 cross-react with genomic DNAs of mouse, rat, hamster, and human. The sperm antigen, lactate dehydrogenase C4 (LDH-C4), is a glycolytic enzyme. Active immunization with LDH-C4 suppressed fertility in mice, rabbits, and baboons. SP-10, which is a testis-specific human sperm protein, is also a promising candidate.     

Improving fertility in beef cow recipients

In the 1970s, bovine embryo transfer (ET) shifted from research in a laboratory environment to commercialization of this technology for beef producers. With the quarantine requirements and expense of importing Continental breeds of cattle from Europe, embryo transfer became the logical means to reproduce greater numbers of these animals at a lower cost. The ET industry grew very rapidly and soon would become what it is today, a common practice utilized by select ranchers and breeders. Research over the years has primarily focused on methods to increase the number of ovulations and fertilized ova from the donor female, but the total number of transferable embryos has not changed markedly in the last 20 years. More recent advances have been in the area of in vitro production of embryos that allow for greater numbers of embryos to be produced and easier accessibility to incorporate technologies such as sexed sperm, sperm injection, or transgenics. This paper will focus on the second part of the equation, the recipient, and decisions that will enable both the customers and practitioners to most efficiently utilize embryos from superovulation, in vitro production, or nuclear transfer, so that the maximum number of pregnancies can be produced.     

Variations in historical natural fertility patterns and the measurement of fertility control

This paper looks at 2 main issues: 1) Henry's definition of natural fertility--that which is not controlled within marriage in a parity-specific way; and 2) the use of standard age-specific marital fertility schedules to measure the extent of fertility control. The authors note a number of conceptual difficulties inherent in Henry's definition and which detract from its usefulness. In particular, prolonged lactation and taboos against sexual intercourse are capable of depressing fertility within marriage, while still allowing it to be described as natural. This paper explores some of the consequences of the identified difficulties for the measurement of fertility control within marriage. Regional as well as temporal variations are to be expected in the pattern of marital fertility. The factors affecting natural fertility may be broadly divided into the physical and the psychological. Needed are a variety of standard marital fertility schedules specific to the underlying fertility conditions of the particular population under investigation. The universal applicability of a single standard is placed in doubt. The greatest problem, however, with the application of the idea of natural fertility to historical populations is that its definition rests upon a number of behavioral characteristics amongst a population, whereas its identification must normally proceed in reverse, arguing backwards from the pattern observed to the behavioral processes and conditions which might have produced that pattern. The arguments presented are illustrated by a detailed example drawn from the fertility patterns of Britain, Denmark and Sweden.     

Role of progestogens for the prevention of premature birth

Premature birth represents a major cause of perinatal morbidity and mortality. The short- and long-term sequelae of prematurity have serious consequences for newborn survival and health in later life. In addition, prematurity is a major problem with regard to health expenditure. Despite major progress in obstetrics, perinatology and neonatology, the percentage of premature birth persists and there is even a tendency towards a slight increase. Therefore, besides screening programmes for the detection of vaginal infections, additional therapeutic opportunities must be sought. According to previously published data, vaginal progesterone and intramuscular 17alpha-hydroxyprogesterone caproate should be considered possible treatment options for the prevention of preterm delivery.     

Model for the feedback control system of bacterial growth. II. Growth in continuous culture

A mathematical model is developed that describes substrate limited bacterial growth in a continuous culture and that is based upon the conceptual framework elaborated in a previous paper for describing the feedback control system of cell growth [S. Bleecken, (1988). J. theor. Biol. 133, 37.] Central to the theory are the ideas that the limiting substrate is converted into low molecular weight building blocks of macromolecular synthesis which again are converted into biomass (RNA and protein) and that the rates of RNA and protein synthesis are controlled by the intracellular concentration of building blocks. It is shown that a continuous culture can be simulated by two interconnected feedback control systems the actuating signals of which are limiting substrate concentration and the intracellular concentration of building blocks, respectively. Three types of steady-states are found to appear in a continuous culture, besides the well-known stable steady-state of the whole culture there exist two batchlike steady-states of the biotic part of the culture which are metastable. The model is used to analyse the steady-states and their stability properties as well as the dynamic responses of biomass, RNA, protein, building block and substrate concentrations to changes in environmental conditions. Especially the inoculation of a continuous culture and the effects of step changes in dilution rate, inlet substrate concentration and growth temperature are studied in detail. Relations between the growth behaviour of a single cell and that of a continuous culture are derived. The RNA to protein ratio is introduced as a rough measure of the physiological state of cells and it is shown that a cell reacts to environmental changes with a simple pattern of basic responses in growth rate and physiological state. There are reasons to assume that the model presented is the minimal version of a structured model of bacterial growth and represents an optimum compromise between biological relevance and mathematical practicability.     

Improving in vitro continuous cultivation of Plasmodium cynomolgi,a model for P. vivax

The absence of a routine continuous in vitro cultivation method for Plasmodium vivax, an important globally distributed parasite species causing malaria in humans, has restricted investigations to field and clinical sampling. Such a method has recently been developed for the Berok strain of P. cynomolgi, a parasite of macaques that has long been used as a model for P. vivax, as these two parasites are nearly indistinguishable biologically and are genetically closely related. The availability of the P. cynomolgi Berok in routine continuous culture provides for the first time an opportunity to conduct a plethora of functional studies. However, the initial cultivation protocol proved unsuited for investigations requiring extended cultivation times, such as reverse genetics and drug resistance. Here we have addressed some of the critical obstacles to this, and we propose a set of modifications that help overcome them.     

Sperm specific proteins-potential candidate molecules for fertility control

The increase in population growth rate warrants the development of additional contraceptive methods that are widely acceptable, free from side effects and less expensive. Immunocontraception, and in particular the targeting of antibodies to gamete-specific antigens implicated in sperm egg binding and fertilization, offers an attractive approach to control fertility. The development of a contraceptive vaccine based on sperm antigen represents a promising approach to contraception. In mammals, fertilization is completed by the direct interaction of sperm and egg, a process mediated primarily by sperm surface proteins. Sperm have proteins that are unique, cell specific, immunogenic and accessible to antibodies. A few of the sperm specific proteins have been isolated and characterized. The antibodies raised against the sperm specific antigens have proved to be extremely effective at reducing sperm-egg interaction in vitro; fertility trials in sub-human primates would eventually prove the effectiveness of the sperm antigens in terms of contraceptive efficacy.     

Endometrial disease after treatment with oestrogens and progestogens in the climacteric.

A prospective study of 745 women receiving different regimens of hormone treatment for the climacteric for a total of 21 736 months was performed. There was a lower incidence of endometrial hyperplasia in biopsy specimens in the women receiving cyclical low-dose oestrogen by mouth than in those receiving cyclical high-dose oestrogen by mouth. The incidence of abnormalities in the women receiving sequential oestrogen and progestogen was lower than in either of these two groups. Among the women receiving subcutaneous oestrogen implants the incidence was higher still, but over half of the abnormal specimens were from women who had not taken their progestogen. The incidence of hyperplasia fell with longer courses of progestogen, and no hyperplasia was found in patients taking progestogen for over 10 days each month. The incidence of adenomatous and atypical hyperplasia is significantly reduced by a progestogen when taken for 10 or more days monthly. The absence of vaginal bleeding or of a regular bleeding response does not guarantee histologically normal endometrium in patients taking oestrogens without progestogen.     

Effect of two long acting injectable progestogens on lactation in the human.

The effects of Depoprovera and Deladroxone were studied in humans, on certain milk components as well as on the growth of the nursed infants. Both drugs caused reduction in milk yield. Both drugs caused an increase in the concentration of milk total proteins, however. Depoprovera caused an increase while Deladroxone caused a decrease in the total amount of milk proteins per feed. Depoprovera showed no effect while Deladroxone caused an increase in the concentration of milk lipids; however, both drugs caused reduction in the total amount of milk lipids per feed. Both drugs showed no effect on the concentration of milk lactose, but caused reduction in the total amount of milk lactose per feed. The percentage increase in weight of nursed infants was decreased by Depoprovera, but not affected by Deladroxone.     

Developing the control criterion for continuous culture of microorganisms

A short survey and critical analysis of previously proposed criteria for growth control of populations of microorganisms in the chemostat are presented. Based on the analysis of a mathematical model of the steady-state of a microbial population in the chemostat, an adequate control criterion is suggested, along with a method to identify the corresponding regulating factors. The new control criterion is expressed as a product of the factor transformation coefficient and the biomass sensitivity coefficient (SC) with respect to the change of the factor at the chemostat inlet (referred to in the sequel as the biomass SC). The control criterion determines the strength of the control exerted by this or that factor. The method of determination of the regulating factors consists in experimental determination of the real SCs for factors and the biomass and in calculating on this basis the corresponding ideal SCs for constant factor transformation coefficients. The ideal SCs are shown to add up to an integer value, a constraint that we call "quantization" relationships. Such relationships are used to test the completeness of the drawn list of control factors. The proposed method was applied to our own and literature data.