bluuebunny/crossref_metadata_2025 huggingface dataset:
WFH – the cornerstone of global development: 45 years of progress
Authors: SKINNER M. W.
Published: May 2008

Summary.  The World Federation of Hemophilia (WFH) has been the cornerstone of global development for 45 years. The WFH has identified and optimized the essential elements of a model for the development of a sustainable national care programme. The five elements of the WFH Development Model are integrated and interdependent: ensuring accurate laboratory diagnosis, achieving government support for a national programme, improving the care delivery system, increasing the availability of treatment products and building a strong national patient organization. It can been demonstrated that patient organizations, healthcare providers and the Ministry of Health working together in coalition is essential to achieving sustainable care. Equally important, the provision of care by a multidisciplinary team of trained professionals within a comprehensive care setting is fundamentally important to optimize outcomes. Using data from the WFH Global Survey, it is evident that the WFH Development Model brings about sustainable improvements in care. To support the Model, the WFH has created a vast range of tools, guides and programmes tailored to specific development needs. The Global Alliance for Progress is the preeminent WFH development program. Five years of outcomes data document a narrowing of the care gap between developed and developing nations. To ensure the continued advance towards the WFH vision of Treatment for All, it is vital that global collaboration occur on the research front as well. The WFH is well positioned to meet the challenges ahead and to continue serving as the cornerstone of global collaboration and development.
Back to the future: a recent history of haemophilia treatment
Authors: MANNUCCI P. M.
Published: May 2008

Summary.  In the last few decades, the management of patients with haemophilia has witnessed dramatic improvements, through the larger availability of safe plasma‐derived and recombinant products for replacement therapy. Another important step forward is the progressively larger‐scale implementation of primary prophylaxis in children. Currently, the main problem in patients with haemophilia is the onset of antibodies inactivating the infused clotting factor (inhibitors), even though immune tolerance regimens that are able to eradicate inhibitors and the availability of products that bypass the intrinsic coagulation defects have dramatically improved the management of these patients. Cure of haemophilia through gene transfer is being attempted, but relatively, it is far from being implemented on a large scale. It is likely that further improvements in replacement therapy will occur in the near future, through the availability of new‐therapeutic tools such as factors VIII and IX with longer half‐lives, more potent bypassing agents and factors extracted from the milk of transgenic animals.
von Willebrand disease update: diagnostic and treatment dilemmas
Authors: BOLTON‐MAGGS P. H. B. , LILLICRAP D. , GOUDEMAND J. , BERNTORP E.
Published: May 2008

Summary.  Although von Willebrand disease (VWD) is now well‐described, many facets of diagnosis and management continue to be debated. The diagnosis of type 1 disease can be difficult but recent genetic analyses help to distinguish many factors which can influence von Willebrand factor (VWF) levels and bleeding phenotype. Type 2 disease (functional abnormalities) includes a particularly interesting group of disorders with faulty binding between VWF and FVIIIC (Normandy) where treatment methods need careful consideration. Type 3 VWD is the most severe form of VWD and a new international study is underway to examine the use of prophylaxis.
Laboratory issues in bleeding disorders
Authors: RODEGHIERO F. , RUIZ‐SÁEZ A. , BOLTON‐MAGGS P. H. B. , HAYWARD C. P. M. , NAIR S. C. , SRIVASTAVA A.
Published: May 2008

Summary. Selected laboratory issues critical for the appropriate diagnosis of haemophilia A and B, von Willebrand’s disease (VWD) and more rare bleeding disorders (RBD) are discussed from a worldwide perspective. The overall picture that emerges is on the whole reassuring. Even in non‐Western countries like Latin America, most cases of haemophilia are appropriately diagnosed. Moreover, national and international laboratory training workshops are further improving the diagnostic capabilities also in less severe disorders. Most of the RBD can be appropriately diagnosed with relatively simple tests wherever a high clinical suspicion is present. Moreover, minimal requirements for a useful clinical diagnosis are not too far from the capabilities of majority of non‐Western countries. The most needed areas concern VWD and platelet function disorders, which suffer from inadequate diagnostic standardization, hampering widespread diagnostic capability in both Western and non‐Western countries.
Orthopaedic management of haemophilia arthropathy of the ankle
Authors: PASTA G. , FORSYTH A. , MERCHAN C. R. , MORTAZAVI S. M. J. , SILVA M. , MULDER K. , MANCUSO E. , PERFETTO O. , HEIM M. , CAVIGLIA H. , SOLIMENO L.
Published: May 2008

Summary. Joint bleeding, or haemarthrosis, is the most common type of bleeding episode experienced by individuals with haemophilia A and B. This leads to changes within the joints, including synovial proliferation, which results in further bleeding and chronic synovitis. Blood in the joint can also directly damage the cartilage, and with repeated bleeding, there is progressive destruction of both cartilage and bone. The end result is known as haemophilic arthropathy. The joints most commonly affected are the knees, elbows and ankles, although any synovial joint may be involved. In the ankle, both the tibiotalar and subtalar joints may be affected and joint bleeding and arthropathy can lead to a number of deformities. Haemophilic arthropathy can be prevented through regular factor replacement prophylaxis and implementing physiotherapy. However, when necessary, there are multiple surgical and non‐surgical options available. In early ankle arthropathy with absent or minimal joint changes, both radioisotopic and chemical synoviorthesis can be used to reduce the hypertrophied synovium. These procedures can decrease the frequency of bleeding episodes, minimizing the risk of articular cartilage damage. Achilles tendon lengthening can be performed, in isolation or in combination with other surgical measures, to correct Achilles tendon contractures. Both arthroscopic and open synovectomies are available as a means to remove the friable villous layer of the synovium and are often indicated when bleeding episodes cannot be properly controlled by factor replacement therapy or synoviorthesis. In the later stages of ankle arthropathy, other surgical options may be considered. Debridement may be indicated when there are loose pieces of cartilage or anterior osteophytes, and can help to improve the joint function, even in the presence of articular cartilage damage. Supramalleolar tibial osteotomy may be indicated in patients with a valgus deformity of the hindfoot without degenerative radiographic findings. Joint fusion, or arthrodesis, is the treatment of choice in the advanced stages of ankle arthropathy although total ankle replacement is currently available. Early ankle replacement components were associated with a poor outcome, but as implant designs have improved, there have been successful outcomes achieved. As the ankle is a commonly affected joint in many individuals with haemophilia, it is important to add to the knowledge base to validate indications and timing of surgical and non‐surgical interventions in ankle arthropathy.
Mild/moderate haemophilia A: new insights into molecular mechanisms and inhibitor development
Authors: D’OIRON R. , PIPE S. W. , JACQUEMIN M.
Published: May 2008

Summary.  In mild/moderate haemophilia A (MHA) patients, many factor VIII (FVIII) gene defects, mainly missense mutations, have been identified and greatly improved the understanding of the structure and function of FVIII molecule. Characterization of the molecular mechanisms involved in MHA has helped to identify regions critical for proper FVIII biosynthesis, thrombin activation, intramolecular stability as well as binding regions for important intermolecular interactions with von Willebrand factor, factor IXa and the phospholipid surface. Some missense mutations were also recognized as contributing factors to inhibitor development in MHA, in parallel to acquired factors such as inflammatory state or intensity of treatment. Treatment of MHA with inhibitor patients raises questions on how best to stop or prevent bleeding episodes and eradicate the inhibitor. Longitudinal data collection is currently being conducted in France and Belgium to enhance our knowledge in this field and to further help make treatment decision. The description of mutations in MHA finally contributed to the identification of epitopes involved in the immune response to FVIII. In some patients, the epitope specificity of inhibitor antibodies recognizing normal exogenous FVIII alone and not patient (‘self’) FVIII was described. This distinguished epitope specificity could also be demonstrated at the T‐cell clonal level. One might expect that these molecular studies will have a major impact on development of new FVIII products in the future.
Ethical considerations in clinical investigation: exploring relevance in haemophilia research
Authors: DIMICHELE D. M.
Published: May 2008

Summary.  Painful controversy has so far been largely absent from the history of haemophilia‐related clinical research. However, the investigative methods now needed to realize evidence‐based clinical practice, therapeutic advance, and a progressive standard of care for patients worldwide will be accompanied by the potential for ethical dilemma and transgression. From the current vantage point, three primary ethical issues merit special consideration: (i) the therapeutic misconception inherent to all clinical research and the randomized trial in particular; (ii) high risk and potentially non‐beneficial novel technology research in children; and (iii) a collaborative partnership approach to research in the developing world. This study will focus on a discussion of each of these, drawing from the research ethics literature to offer a potential template for future deliberations in clinical trial design.
The role of the physiatrist in the haemophilia comprehensive care team in different parts of the world
Authors: HEIJNEN L. , DIRAT G. , CHEN L. , TULAAR A. B. M. , MOYSISYAN L. , NASSAR N. M. M. , BATISTELLA L. R.
Published: May 2008

Summary.  The role of the physiatrist, as a member of the multidisciplinary haemophilia comprehensive care team, is to prevent and treat activity limitations and restriction of participation on the part of the patient. . This role is threefold: (i) provide education to the patients, families and healthcare providers to detect disabling injuries and take adequate precautions; (ii) provide specialized treatment of musculoskeletal disabilities striving for the highest level of functionality and (iii) Stimulate the patient’s full participation in socio‐economic activities of his country. Prominent physiatrists from different parts of the world describe the situation in Armenia, China, Egypt, France, Indonesia (and the Philippines), the Netherlands and South America.
New approaches in the measurement of coagulation
Authors: INGERSLEV J. , SØRENSEN B. , CASTAMAN G. , LLOYD J. V. , VARON J. D. , SAVION N.
Published: May 2008

Summary.  In this session contributors present recent developments in laboratory tools for investigation of haemorrhagic disorders as well as their relative utility in clinical research. In an overview of B. Sørensen the present knowledge is summarized on the dynamic properties of whole blood fibrin formation as studied by changes in whole blood elasticity on a thrombelastometry system. Additionally, fibrin formation dynamics using simple APTT methods are presented. G. Castaman reviews the pathophysiology of von Willebrand’s disease (VWD) and explains which tests are best used in diagnosis and subclassification of VWD accounting for recent developments. This presentation also describes the treatment technologies available today and their implications in clinical management of bleeding episodes in VWD. J. Lloyd addresses the assay discrepancy phenomenon that is found in some of our patients suffering from mild haemophilia A. Assay discrepancy most often means a much lower factor VIII:C value by a two‐stage or chromogenic assay for factor VIII:C compared to the activity recorded by the one‐stage clotting system for factor VIII:C. In rare cases, the opposite phenomenon exist. The presentation includes data from 16 Australian families with discrepant results. D. Varon reports on an assay for study of platelet function in whole blood under flow conditions. The equipment is described as a cone‐and‐plate(let) analyser in which the adhesion and aggregation of platelets onto a polystyrene surface is studied under arterial flow conditions. Basically, it is anticipated that proteins such as VWF and fibrinogen of flowing blood is attached to the polystyrene surface where they build up a thrombogenic surface. In the study of the author platelets were pre‐activated with agonists and platelet deposits were determined after passage of whole blood for a pre‐set time interval. Data presented suggest that the assay is sensitive to platelet numbers as well as qualitative changes in platelets themselves, and several examples of disorders characterized by enhanced as well as reduced platelet aggregating activities illustrates the sensitivity of the method.
Redundancy renders the glycoprotein 96 receptor scavenger receptor A dispensable for cross priming in vivo
Authors: Tewalt Eric F. , Maynard Jason C. , Walters Julie Jo , Schell Amanda M. , Berwin Brent L. , Nicchitta Christopher V. , Norbury Christopher C.
Published: May 2008

CD8+ T cells (TCD8+) differentiate into effector cells following recognition of specific peptide–major histocompatibility complex (MHC) class I complexes (pMHC‐I) on the surface of professional APCs (pAPCs), such as dendritic cells. Antigenic pMHC‐I can be generated from two spatially distinct sources. The direct presentation pathway involves generation of peptide from protein substrate synthesized within the cell that is presenting the pMHC‐I. Alternatively, the cross presentation pathway involves presentation of antigen that is not synthesized within the presenting cell, but is derived from exogenous proteins synthesized within other donor cells. The mechanisms by which cross presentation of exogenous antigens occur in vivo remain controversial. The C‐type lectin scavenger receptor A (SR‐A) has been implicated in a number of potential cross presentation pathways, including the presentation of peptide bound to heat shock proteins, such as glycoprotein 96 (gp96), and the transfer of pMHC‐I from a donor cell to the pAPC. We demonstrate here that initiation of TCD8+ responses is normal in mice lacking SR‐A, and that the redundancy of ligand binding exhibited by the SR family is likely to be an important mechanism that ensures cross presentation in vivo. These observations emphasize the requirement to target multiple receptors and antigen‐processing pathways during the rational design of vaccines aimed at eliciting protective TCD8+.
Sex Determination and Differentiation of the Mammalian Gonad
Authors: Short R. V.
Published: May 2008

There is growing evidence to suggest that the presence of a single gene on the Y chromosome, which also codes for the expression of the H‐Y antigen, causes the primordial gonad to develop structurally as a testis: in the absence of this gene, an ovary is formed. Whether the gonad subsequently becomes capable of producing viable gametes depends on the sex chromosome makeup of the germ cells that migrate into it; XY or XO germ cells seem to be capable of developing into either oocytes or spermatocytes, depending on the environment, whereas germ cells with two X chromosomes can only develop as oocytes, and will not survive in a testicular environment. The H‐Y antigen probably plays no role in the sexual differentiation of the germ cell.

There is another gene on the Y chromosome that determines testis size, and testes: body weight ratios vary widely in different mammals. Amongst the higher primates the gorilla has the lowest ratio (0.018%), man is intermediate (0.079%) and the chimpanzes have the highest (0.269%). Testis size is predominantly determined by the amount of tubular tissue, and appears to be closely related to copulatory frequency, and hence to the mating behaviour of the species. It is important to take these marked species differences in testis size into account when using primate models for human male contraceptive research and development.
Homologies of Structure and Function in Mammalian Testes and Ovaries
Authors: Ross Griff T. , Lipsett Mortimer B.
Published: May 2008

In mammalian testes and ovaries, gametogenic and steroidogenic compartments interact in producing gametes and secreting sex steroid hormones. Components of these compartments share a number of structural and functional homologies. In the gametogenic compartments, Sertoli cells in testicular tubules and granulosa cells in ovarian follicles form diffusion barriers between germ cells and substances in blood and lymph, secrete luminal fluid and synthesize proteins and steroid hormones. However, steroid hormone concentrations in spermatic and ovarian veins represent the secretory activities of steroidogenic compartments.

Interstitial cells in testes and ovaries synthesize and secrete androgens but whether they are the major source of estrogens in ovarian venous blood remains controversial. There are data which suggest that androgens and estrogens, acting on Sertoli cells and granulosa cells, mediate the role of gonadotrophins in induction and maintenance of gametogenesis in testis and ovary. Collectively, the numerous homologies of structure and function provide evidence for conservation and adaptation of mechanisms in mammalian gonads.
Steroidogenesis by Granulosa and Sertoli Cells
Authors: Dorrington Jennifer H. , Fritz I. B. , Armstrong D. T.
Published: May 2008

Granulosa and Sertoli cells have been isolated from the gonads of immature rats, and have been maintained in monolayer cultures in a chemically‐defined medium. The hormonal requirements of these cell types for the synthesis of steroids have been studied: Granulosa cells contain cholesterol side‐chain cleavage activity and synthesise progesterone when cultured in the presence of FSH and testosterone (or DHT). Sertoli cells on the other hand cannot synthesise steroids de novo. Granulosa and Sertoli cells are similar in that they are unable to convert significant amounts of progesterone to androgens. In the presence of exogenous testosterone as substrate, granulosa cells and immature Sertoli cells can synthesise estradiol and estrone when stimulated with FSH. In summary, FSH stimulates estrogen synthesis from testosterone in both cell types, and acts synergistically with testosterone (or DHT) to stimulate progesterone synthesis in granulosa cells. FSH is therefore involved in controlling the steroid environment within the gonads.
Nature and Mechanisms of Action of Inhibin: Perspective in Regulation of Male Fertility
Authors: Franchimont P. , Demoulin A. , Verstraelen‐Proyard J. , Hazee‐Hagelstein M. T. , Walton J. S. , Waites G. M. H.
Published: May 2008

Inhibin extracted from human seminal plasma and from rete testis fluid is a protein substance. Two forms of inhibin exist in RTF and each has a different molecular weight. The species of higher molecular weight systematically yields a product of lower molecular weight during chromatography. This phenomenon could represent depolymerization of the molecule, an associated transport protein or alternatively a precursor form of inhibin.

The inhibin preparations utilized selectively lowered the levels of FSH as assessed both in vivo and in vitro. This action was not totally specific since increasing doses of inhibin also produced a lowering of the levels of LH. In contrast, these preparations did not influence the secretion of TSH, growth hormone or prolactin in vivo or in vitro.

A direct effect of inhibin on pituitary cells has been clearly established by demonstrating a reduction in the release of FSH in response to GnRH and its synthesis in the pituitary cells. Additional direct effects on the hypothalamus and on gametogenesis in the testis remain to be excluded. On the basis of selective effects of inhibin on FSH secretion, one could envisage the utilization of this hormone as an antifertility agent.
Effects of Testicular and Ovarian Inhibin‐Like Activity, Using In Vitro and In Vivo Systems
Authors: de Jong F. H. , Welschen R. , Hermans W. P. , Smith S. D. , van der Molen H. J.
Published: May 2008

Inhibin‐like activities in charcoal‐treated bovine follicular fluid (FF) and medium from cultured Sertoli cells (SCCM) were assayed in an in vitro bioassay system, using cultured pituitary cells. Addition of both fluids resulted in parallel dose‐dependent decreases of the concentration of follicle‐stimulating hormone (FSH) in the medium, both in the presence or absence of luteinizing hormone‐releasing hormone (LH‐RH).

A single injection of FF into immature and adult male and female rats resulted in decreased peripheral levels of FSH, but not of LH, after 4 or 8 h. This decrease was larger and occurred faster in adult female rats than in prepubertal female animals. Injection of FF into adult female rats, immediately after unilateral ovariectomy (ULO) prevented the specific increase of FSH levels, occurring in control animals. This suppression could not be obtained after treatment with steroids.

Daily treatment of adult female or immature male rats for periods longer than 5 days did not result in prolonged suppression of circulating FSH concentrations; LH levels were significantly increased. The female animals showed cyclic vaginal smear changes and normal ovulation; in the male rats testis weight and numbers of spermatogenic cells were reduced.

It is concluded that testicular and ovarian inhibin‐like activities have similar properties. Injections of FF into male and female rats cause similar effects on FSH and LH. The effect of FF in ULO‐animals suggests that inhibin could play a role in the short‐term regulation of the number of developing follicles in the ovary. Injection of FF into male rats causes a probably transient impairment of spermatogenesis through an initial suppression of FSH.
Some Comments on the Use of Steroid Hormones for Male Contraception
Authors: Neumann F. , Nickolson R. C. , Schenck B. , Steinbeck H.
Published: May 2008

Four different approaches are discussed in relation to the use of androgens or androgen/progestin combinations for the control of male fertility. Special attention is drawn to new synthetic steroids which possess both strong androgenic and progestational activities.
Progestin Receptors in the Anterior Pituitary and Hypothalamus of Male Rats
Authors: Naess Oddvar , Attramadal Arne
Published: May 2008

Properties of progestin receptors in the pituitary and hypothalamic cytosol fraction of male rats were studied using the highly potent progestin (3H) R 5020 (17,20‐dimethyl‐19‐nor‐pregna‐4,9‐diene‐3,20‐dione). As shown by sucrose gradient analysis, specific binding of (3H) R 5020 is associated with components migrating at 7 S and 4 S. The isoelectric point of the binding components were 5.8. The binding of (3H) R 5020 is highly specific since it is easily displaced by unlabelled R 5020 and progesterone. The affinity of unlabelled testosterone, 17β‐estradiol and cyproterone acetate was much lower, whereas unlabelled cortisol had no affinity for the progestin receptor. The dissociation constant of pituitary R 5020 binding is approximately 1 times 10‐9 M.

Pretreatment of the animals with 17β‐estradiol‐valerate greatly increased the progestin receptor levels in the tissues.
Inhibition of Leydig Cell Steroidogenesis: Effect of Actinomycin D Before and After Preincubation of Leydig Cells In Vitro
Authors: Cooke B. A. , Janszen F. H. A. , van Driel M. J. A.
Published: May 2008

The effect of preincubating purified Leydig cells in Eagle's medium and the subsequent effect of the mRNA synthesis inhibitor actinomycin D on LH‐stimulated testosterone synthesis has been investigated. The inhibitory effect obtained was found to decrease with the period of preincubation; with 0, 1, 2 and 3 h preincubation before the addition of LH (100 ng/ml) 36.5 ± 3.9, 31.2 ± 2.5, 17.8 ± 3.8 and 13.6 ± 2.9% inhibition occurred respectively when actinomycin D (6.4 μM) was added and the cells were incubated for 2 h (means ± SEM, n = 5). During the first hour of incubation with LH and actinomycin D no inhibition occurred in cells that had been preincubated for 3 h.

These results suggest that during preincubation and independently of LH, synthesis of intermediates (possibly mRNA(s)) required for stimulation of steroidogenesis may take place and that subsequent stimulation of steroidogenesis by LH occurs without further de novo mRNA synthesis.
Inhibitory Effect of LHRH and Its Agonists on Testicular Gonadotrophin Receptors and Spermatogenesis in the Rat
Authors: Labrie Fernand , Auclair Claude , Cusan Lionel , Kelly Paul A. , Pelletier Georges , Ferland Louise
Published: May 2008

Treatment of adult male rats with the potent LHRH agonists [D‐Leu6, des‐Gly‐NH210]LHRH ethylamide or [D‐Ala6. des‐Gly‐NH210]LHRH ethylamide led to a marked reduction of testicular LH and prolactin receptor levels accompanied by decreased plasma testosterone levels and testis, seminal vesicle and prostate weight. Maximal inhibitory effects were seen at a dose of 50 ng. After a single injection, maximal inhibitory effects were seen at 2–4 days with return toward normal levels at later time intervals. Similar results were obtained with LHRH itself although 5 μg was required for maximal effects. When the LHRH analog was administered twice a week at the 100 ng dose, degenerative signs appeared in the seminiferous tubules after one week while at four weeks, degenerative changes were so advanced that almost all germ cells had disappeared leaving only Sertoli cells.
Effect of Gonadotropins and LH‐RH on Functional Differentiation of Immature Monkey Testis
Authors: Arslan M. , Zaidi A. A. , Qazi M. H.
Published: May 2008

Response of the immature monkey testis to gonadotropins and LH‐RH has been assessed by measuring plasma and testicular testosterone concentrations. Administration of 50 μg of LH or FSH for 5 days to immature animals, did not significantly increase the plasma or testicular testosterone levels. When a daily dose of 200 μg of LH or 150 IU hCG was given, there was a marked increase in testosterone levels in the plasma and the testicular tissue. In vitro experiments indicate that whereas the testicular tissue of normal and FSH‐primed monkeys is refractory to gonadotropins, the testicular tissue of monkeys sensitized with LH shows enhanced androgenesis when incubated with LH. Unlike the adult, the plasma testosterone levels did not increase following an intravenous injection of 2 μg of LH‐RH. This amount of LH‐RH, however, produced a measurable increase in plasma testosterone in gonadotropin‐primed immature monkeys.
The Radioimmunoassay of Testosterone, 5α‐Dihydrotestosterone and Their Precursors in the Human Testis
Authors: Hammond G. L. , Ahonen V. , Vihko R.
Published: May 2008

A method is described for the simultaneous radioimmunoassays of pregnenolone, progesterone, 17α‐hydroxyprogesterone, androstenedione, testosterone and 5α‐dihydrotestosterone in 100 mg samples of human testis tissue. The specificity is illustrated by determining the chromatographic elution profiles of steroid extracts by radioimmunoassay. The C.V. of individual assays were assessed by analysing 5 samples taken from the same testis, and illustrates the high reproducibility of the method, and homogeneity of samples. The stability of endogenous testicular steroids was assessed in relation to time at room temperature, and marked changes in composition occurred within 5 h, indicating the limitations in using autopsy samples. Testicular steroid concentrations were determined in testes from 16 patients, 10 of whom had been treated with estrogen (polyestradiol phosphate) 1–5 days before orchiectomy. No effect of estrogen treatment on testicular concentrations of steroids was observed, despite the previously established decline in levels of these steroids in the spermatic veins of similar patients.
Temperature Dependence of Sertoli Cell Function
Authors: Hagenäs L. , Ritzén E. M. , Svensson J. , Hansson V. , Purvis K.
Published: May 2008

Spermatogenesis as well as Sertoli cell function, monitored by ABP secretion, is severely impaired at 37°C in vivo and in vitro. A closer understanding of the biochemical mechanisms behind this phenomenon may lead to future methods for fertility control.

The cryptorchid Sertoli cell was shown to be exposed to normal or increased levels of the two main stimulatory hormones, testosterone and FSH. Androgen receptor concentrations in hypophysectomized rat testes were not changed by cryptorchidism. However, FSH and to some extent LH receptors showed a gradual decline during 28 days of cryptorchidism. Even in the absence of hormones, Sertoli cells in vitro produced less ABP at 37 than at 32°C. This shows that 1) Testicular FSH receptors can be practically eliminated in vivo. 2) The basal secretion of protein by the Sertoli cell, in the absence of hormones, is impaired at elevated temperature. An elucidation of the biochemistry involved in that impairment may also yield possible points of attack in the search for a male contraceptive.
The Mechanism of Transport of Testosterone through the Walls of the Seminiferous Tubules of the Rat Testis
Authors: Setchell B. P. , Laurie M. S. , Main S. J. , Goats G. C.
Published: May 2008

A specific saturable carrier‐mechanism probably involving facilitated diffusion has been shown to be involved in the transport of testosterone into seminiferous tubule fluid (STF) and rete testis fluid (RTF). This carrier does not transport DHT and its capacity for testosterone is not affected by increasing the concentration of DHT in the blood.
The Presence of an Androgen Controlled Phospholipase A in Rat Epididymis
Authors: Bjerve Kristian S. , Reitan Liv Jorunn
Published: May 2008

The presence of a phospholipase A (EC 3.1.1.4) and a lysophospholipase (EC 3.1.1.5) has been demonstrated in a postmitochondrial preparation from rat epididymis. Three different enzyme assays using both endogenous and exogenous substrates were employed. Phospholipase A was the rate limiting enzyme in the hydrolysis of lecithin to sn‐3‐glycerophosphorylcholine which also was the main product of the hydrolysis. The enzyme preparation did not show any phospholipase D (EC 3.1.4.4) nor glycerophosphinicocholine glycerophosphohydrolase (EC 3.1.4.2) activity. A small amount of phosphorylcholine was liberated during the hydrolysis indicating the presence of a glycerophosphinicocholine cholinephosphohydrolase (EC 3.1.4.38).

The phospholipase A activity per mg of protein was 10 times higher in the cauda than in the caput epididymidis, while the corpus epididymidis possessed an intermediate specific activity. Castration reduced the specific activity of the enzyme with about 50% in the caput and with about 95% in the cauda epididymidis. Testosterone supplementation restored the enzyme activity nearly to normal in the castrated animals.

This work suggests that the androgen control of the epididymal concen tration of sn‐3‐glycerophosphorylcholine is exerted via a control of the phospholipase A activity in the epididymal epithelial cells. It is suggested that this enzyme controls the concentration of epididymal glycerophosphorylcholine and the supply of long chain fatty acids to epididymal spermatozoa.
Purification and Localization of Acidic Epididymal Glycoprotein (AEG): A Sperm Coating Protein Secreted by the Rat Epididymis
Authors: Lea Oscar A. , Petrusz Peter , French Frank S.
Published: May 2008

A protein designated acidic epididymal glycoprotein (AEG) was purified from rat epididymis using ion exchange chromatography on DEAE‐Sephadex, gel filtration in Sephadex G‐75 and affinity chromatography on Concanavalin‐A Sepharose. AEG is a major secretory product of the epididymis making up 2–3 per cent of total soluble protein. Antibody to AEG was raised in rabbits and purified by affinity chromatography on AEG‐Sepharose. Quantitation of AEG in cytosol using “rocket” immunoelectrophoresis showed AEG to increase in epididymal segments from caput to cauda. Ligation of the midcorpus decreased AEG in the cauda. Localization of AEG using an immunoperoxidase method revealed that it is secreted largely by the epithelium of caput and corpus beginning with the region distal to the initial segment. It appears to be secreted by a specific cell type, probably the so‐called “principal” cell. Specific staining of AEG was also noted in “clear” cells in the cauda. Spermatozoa become coated with AEG as they leave the initial segment and remain so during passage through the cauda.
Effects of Prostaglandin F2α on Sperm Count, Sperm Motility and Fertilizing Capacity in the Male Rabbit
Authors: Saksena S. K. , Hunt D. M. , Lau I. F.
Published: May 2008

Prostaglandin F2α (PGF2α) incorporated in Silastic‐PVP tubes 2 cm long and one end sealed induced temporary sterility when placed intrascrotally in fertile male rabbits. A significant reduction in sperm number per ejaculate, testicular weight and the number of epididymal sperm accompanied the incidence of sterility which occurred 2–5 weeks after starting the treatment and persisted for 6–10 weeks. During the experimental period, no significant deviation in libido or ejaculate volume compared to sham controls was observed. Prostaglandin F2α might have a local effect on the testis and epididymis, causing disintegration and depletion of the sperm reserve resulting in temporary sterility.
Hormonal Contraception for Men
Authors: Schearer S. Bruce , Alvarez‐Sanchez Francisco , Anselmo Jose , Brenner Paul , Coutinho Elsimar , Latham‐Faundes Anibal , Frick Julian , Heinild Bent , Johansson Elof D. B.
Published: May 2008

Between 1971 and 1977, a public‐sector contraceptive development program organized 35 clinical studies to test whether progestins, alone or with androgens, could be used to develop a new contraceptive for men. This review presents the principal findings from these studies. The studies demonstrated that when high doses of progestins are administered to men. sperm production is suppressed to very low levels in the majority of cases. But full suppression of sperm production in all men could not be achieved even when high doses of progestins were administered alone or in combination with high doses of an androgen. All of the progestins tested were associated with weight gain and transient decreases in libido in some men. Some of the regimens tested caused additional side effects, including gynecomastia and impairment of liver function. It is concluded that none of the 25 regimens investigated to date is suited for further development as a male contraceptive. However, the finding that several of the regimens suppressed sperm production to very low levels – often to azoospermic levels – without producing substantial side effects is encouraging. Based on these findings, it is suggested that other combined regimens of more ***
Histological and Morphometric Studies in Undescended Testes
Authors: Waaler Per Erik
Published: May 2008

The histological pattern, volumetric fractions (VF) of tubular and interstitial tissue and the germinal cells, and the mean tubular diameter (MTD) were studied in 175 biopsies from 134 boys aged 3.5–16.9 years with unilateral or bilateral undescended testes. The findings were compared to those obtained in autopsy material from 67 normal boys aged 0.3–20.6 years. In both groups, the qualitative histological pattern was similar to the findings in other reports. In the normal material, VF of spermatogonia A was relatively stable whereas VF of the total spermatogenesis increased sharply after 10 years of age. In the patients, the mean values of both these variables were markedly decreased in all age groups. VF of tubular tissue and the ratio VF tubular/VF interstitial tissue were relatively stable in childhood and increased after 10 years of age both in the patients and in the normal group. In patients aged 3.5–7.9 years, the testicular volume and the volume of tubular tissue per testis were decreased. The MTD of undescended testes was decreased in patients aged 3.5–5.9 years and over 10 years of age. None of the variables investigated showed significant differences between cases with high (intraabdominal and canalicular) and low retention. The results indicated that impairment of the germinal and Sertoli cell lines were usually present in retained testes after 3.5 years of age. The normal maturational changes of tubular and interstital tissues were retarded or absent in pubertal cryptorchids.
Ductuli Efferentes in Two Cases of Testicular Agenesis
Authors: Cotelli Franco , Ferraguti Marco , Gambacorta Marcello
Published: May 2008

Testicular biopsies of two cases of testicular agenesis were studied under the electron microscope, and revealed structures comparable to ductuli efferentes. The microscopic characteristics of these structures are discussed, with particular attention to the ciliary apparatus.
A Mechanism for the Antiandrogenic Action of Medrogestone1
Authors: Bullock L. P. , Gupta C. , Bardin C. W.
Published: May 2008

The antiandrogenic action of the progestin, medrogestone, in rat and man was ascribed initially to an alteration in testosterone biosynthesis and metabolism rather than to a direct effect via the androgen receptor. However in previous studies we had found that many progestins bind directly to the androgen receptor in mouse kidney and have androgenic, antiandrogenic or synandrogenic activity. It was thus of interest to characterize the effect of medrogestone on androgen action in mouse kidney and to determine if this progestin was bound by the androgen receptor. Medrogestone inhibited the growth response and increase in the activity of β‐glucuronidase and alcohol dehydrogenase induced by exogenous testosterone in the kidney of castrate male mice. It also inhibited the growth response of preputial gland and seminal vesicle. This progestin suppressed nuclear uptake of [3H]androgen in kidney, seminal vesicle and submaxillary gland following the in vivo administration of [3H] testosterone. In vitro, medrogestone directly inhibited [3H]testosterone binding by the androgen receptor in mouse kidney cytosol. To insure that these effects were not unique to the mouse, similar studies were repeated in the rat. In this species, medrogestone also inhibited nuclear androgen accumulation and receptor binding in prostate and seminal vesicle. Thus medrogestone can affect androgen action directly via binding to the androgen receptor in the mouse and rat.
Functional and Structural Aspects of the Rat Seminiferous Tubules after Treatment with Exogenous Cyproterone Acetate, Testosterone, Progesterone and Oestradiol
Authors: Hovatta Outi , Koskimies Aarne I.
Published: May 2008

Cyproterone acetate, testosterone propionate, progesterone and oestradiol were given to adult rats for 30 days, and the effects on the seminiferous tubules were studied. The contractility of the seminiferous tubules was not affected by cyproterone acetate or progesterone, but was totally abolished by testosterone and oestradiol. The effects of these steroids on spermatogenesis were studied histologically and electron microscopically.

Cyproterone acetate was observed to induce a clear‐cut increase in the lipid content of the Sertoli cells and mitochondrial changes in all stages of the cycle of the seminiferous epithelium.

The increase of lipid content was smaller with progesterone. Oestradiol caused an accumulation of phagocytosed lipid material in Sertoli cells. These steroids did not change the protein composition of the rete testis fluid.
Sertoli Cell Function in the Androgen Insensitive (TFM) Rat
Authors: Hansson V. , Purvis K. , Attramadal A. , Torjesen P. , Andersen D. , Ritzén E. M.
Published: May 2008

The Sertoli cells of the androgen insensitive (tfm) rat are capable of producing androgen binding protein (ABP) both in vivo and in vitro. ABP levels in the tfm testis are significantly higher (P < 0.01) than that in normal littermates (NL); 2.9 ± 0.5 (SD) pmoles/mg protein and 63.7 ± 15 (SD) pmoles/testis in the tfm compared to 0.41 ± 0.07 pmoles/mg protein and 34.3 ± 6.7 pmoles/testis in the NL. However, ABP secretion rate in vitro is significantly lower in the tfm testis than that in the NL testis; 0.12 ± 0.02 (SD) pmol/testis per h and 0.31 ± 0.06 pmol/testis per h respectively. Thus, the increased levels of ABP in the tfm testis does not reflect increased ABP secretion, but is due to the atresia of the excurrent ducts and accumulation of seminiterous tubular secretion. The tfm testes show a higher concentration of FSH receptors than that in NL (171 fmoles/mg protein and 57 fmoles/mg protein respectively). However, when FSH binding is calculated per testis, binding capacities in tfm and NL testis are very similar (632 fmoles/testis and 798 fmoles/testis respectively). The present study shows that normal induction of FSH receptors is not dependent on the presence of an androgen receptor and that production and secretion of ABP is taking place in a situation where the target cells are insensitive to physiological doses of androgen.

The reduction in ABP secretion rate in vitro in the tfm rat testis supports previous studies showing that both FSH and androgens are important for normal Sertoli cell function.
Recovery of Spermatogenesis in an Azoospermic Patient after Operation for Bilateral Undescended Testes at the Age of 25 Years
Authors: Comhaire F. , Derom F. , Vermeulen L.
Published: May 2008

A 25 year old man, the partner of a barren marriage of 3 years duration, presented with bilateral inguinal testes, azoospermia and elevated serum gonadotrophin levels. After surgical correction the testes remained in the scrotum and within 16 months the semen contained 22 million spermatozoa per ml. Although the motility and morphology of the spermatozoa remained in the subnormal range, the recovery of spermatogenesis is considered exceptional.
Testicular Steroid Metabolism In Vitro in an XX‐Male
Authors: Kjessler B. , Berg A. Å:son , Fjällbrant B.
Published: May 2008

XX‐males are known to display dysgenetic gonads with failing sperm production. Since defective male gametogenesis has in certain instances been proposed to be related to an aberrant intratesticular steroid biosynthesis (Steinberger et al. 1974), we have analysed the metabolism of [3H] progesterone in vitro in an XX‐male.

The 33‐year‐old patient was sterile and demonstrated high levels of gonadotrophic hormones in the peripheral circulation, though he displayed ordinary male secondary sex characteristics. Testicular biopsy specimens were incubated with [3H] progesterone. This radiolabelled precursor was found to be avidly metabolized along the so‐called “Δ4‐pathway” towards biologically active C19‐androgens in this XX‐male, as in testicular tissue derived from adult control subjects.

Furthermore, the relative metabolism of [3H] progesterone per mg of testicular tissue incubated, was observed to be significantly higher in the dysgenetic gonadal tissue derived from the present XX‐male as compared to the metabolism in the control subjects.

The amount of [3H] 17α‐hydroxyprogesterone synthesized in the XX‐male was very high, and also the ratio of [3H] 20α‐dihydroprogesterone:[3H]‐17α‐hydroxyprogesterone was found to be remarkably small, i. e. a pattern repeatedly observed in other hypergonadotrophic individuals (Kjessler & Berg 1976b).

The present investigation thus demonstrated that intratesticular steroidogenesis along the Δ4‐pathway in vitro may be excellent in dysgenetic gonadal tissue with an XX‐chromosomal constitution.
Effect of Androgens on Antipyrine Metabolism in the Rabbit
Authors: Salvá P. , Laporte J. , Saura E. , Salvá J. A.
Published: May 2008

The inactivation of endogenous steroids and foreign compounds by the liver hydroxylative pathway, can be modified by androgenic substances. The inhibitory or inductory activity, can be estimated by measuring the half‐life of antipyrine. Androgens (testosterone propionate, 5α‐dihydro‐testosterone and mesterolone) reduce antipyrine metabolism in male rabbits. In females, androgens are not inhibitors, but one of them, 5α‐dihydrotestosterone, shows an inductive effect on liver oxidative mechanisms.
The Effect of Caffeine on Rat Epididymal Spermatozoa: Motility, Metabolism and Fertilizing Capacity
Authors: (Frenkel) G. Paz , Kaplan Ruth , Yedwab G. , Homonnai Z. T. , Kraicer P. F.
Published: May 2008

The metabolism, motility and fertilizing capacity of spermatozoa from the caput, corpus and cauda epididymidis were examined. Motility increased from 3% to almost 50% from caput to cauda.

Caput sperm were almost infertile, when inseminated into the uterus. Corpus and cauda sperm fertilized ova in 54 and 60% (respectively) of females, but the number of offspring was below our average colony litter size. Caffeine, 10 mM, had no effect on any of the sperm characteristics measured. No teratogenic effects or long‐term effects on fertility of the offspring were seen.
Four Cases of Low Chiasma Frequency Diagnosed in Semen
Authors: Templado Cristina , Marina S. , Canal F. Suarez , Gil‐Vernet E. , Izquierdo L. , Egozcue J.
Published: May 2008

Four cases of low chiasma frequency have been detected using a technique to study meiosis in semen. Three of the patients showed desynapsis and fragmentation of the bivalents. In the fourth case, desynapsis was probably due to an abnormal despiralization of the bivalents. None of the patients had a spermatogenic arrest. Banding studies did not permit to identify the chromosomal fragments. The incidence of oligochiasmatic males in our semen and testicular biopsy series is about 2.5%. The advantages of the method are discussed.
Cytological Studies of Prostatic Fluids from Men with and without Abnormal Palpatory Findings of the Prostate I. Methodological Aspects
Authors: Johannisson E. , Eliasson R.
Published: May 2008

The exfoliative cytology of fluids from the prostate and seminal vesicles has been examined after staining of smears according to Papanicolaou. The specimens have been classified into three groups depending upon the number of inflammatory cells and the cytological changes observed in the various types of cells present in the fluid.

In a group of 100 men attending the clinic due to barren marriage, the cytological findings in expressed fluid were compared with the palpatory assessment of the prostate and seminal vesicles. The palpatory assessment was regarded normal in 58, uncertain in 32 and clearly abnormal in 10 men. By the cytological examination of the same group, heavy inflammatory changes were found in 13, 14 and 7 individuals respectively.

It is concluded that a careful cytological examination, including an assessment of the whole cellular pattern observed in the smears of the fluid expressed from the prostate and seminal vesicles – if performed using proper techniques for sampling, fixation and staining and interpreted by experienced cytologists – may be a useful complement to the clinical examination in the diagnosis of inflammatory diseases of the male accessory glands.