Permanent Infertility Research Articles

Expression and regulation of the CC-chemokine monocyte chemoattractant protein-1 in rat testicular cells in primary culture.

Testicular inflammation is classically observed in pathogenesis caused by infectious agents, environmental toxins, trauma, or autoimmune reactions and can lead to transitory or even permanent sterility. In these situations, a leukocyte infiltration is generally encountered. Macrophage inflammatory proteins (MIP)-1alpha and -1beta and monocyte chemoattractant protein-1 (MCP-1) are CC-chemokines involved in macrophage and lymphocyte chemoattraction. In the present study, using reverse transcription-polymerase chain reaction, Northern blot, and a specific ELISA, we investigated whether or not these chemokines are present within the testis and whether they are induced by a number of proinflammatory cytokines and lipopolysaccharides (LPS). MIP-1alpha and MIP-1beta were not detected in Sertoli cells, germ cells, peritubular cells, or Leydig cells. In contrast, MCP-1 mRNA and protein were found to be expressed by control isolated peritubular cells, and expression was markedly stimulated by interleukin-1alpha and-1beta (IL-1alpha and IL-1beta), tumor necrosis factor alpha (TNF-alpha), interferon gamma, and LPS. Leydig cells expressed MCP-1 when stimulated by IL-1beta. In contrast, MCP-1 was not found to be produced by Sertoli cells or germ cells as established by Northern blot and ELISA techniques. The kinetics of MCP-1 production by peritubular cells, as demonstrated by expression as early as 8 h poststimulation, are compatible with there being a rapid mobilization of these cells and this chemokine in an inflammatory process. Moreover, MCP-1 production by peritubular cells after half-maximal stimulation by LPS, TNF-alpha, and IL-1beta (2 pg/ml-0.9 ng/ml) is also compatible with the physiologic concentrations of the proinflammatory cytokines generally found in an inflammatory site. It is concluded that MCP-1 is produced by Leydig cells and peritubular cells and that it could be involved in the mobilization and migration of leukocytes observed during testicular inflammation.

Cell death in ovarioles causes permanent sterility in Frieseomelitta varia worker bees

Frieseomelitta varia worker bees do not lay eggs even when living in queenless colonies, a condition that favors ovary development and oviposition in the majority of highly social bees. The permanent sterility of these worker bees was initially attributed to a failure in ovary morphogenesis and differentiation. Using transmission electron microscopy we found that at the beginning of the pupal phase the ovaries of F. varia workers are formed by four ovarioles, each of them composed of 1) a terminal filament at the apex of the ovarioles, containing juxtaposed and irregularly shaped cells, 2) a germarium with clusters of cystocytes and prefollicular cells showing long cytoplasmic projections that envelop the cystocyte clusters, 3) fusiform interfollicular and basal stalk precursor cells, and 4) globular, irregularly contoured basal cells with large nuclei. However, during the pupal phase an accentuated and progressive process of cell death takes place in the ovarioles. The dying cells are characterized by large membrane bodies, electron-dense apoptotic bodies, vacuoles, vesiculation, secondary lysosomes, enlarged rough endoplasmic reticulum cisternae, swollen mitochondria, pycnotic nuclei, masses of chromatin adjacent to the convoluted nuclear envelope, and nucleoli showing signs of fragmentation. Cell death continues in ovarioles even after the emergence of the workers. Once they become nurse bees, the ovaries have become transformed into a cell mass in which structurally organized ovarioles can no longer be identified. In F. varia workers, ovariole cell death most certainly is part of the program of caste differentiation. J. Morphol. 242:271–282, 1999. © 1999 Wiley-Liss, Inc.

Cell death in ovarioles causes permanent sterility in Frieseomelitta varia worker bees.

Frieseomelitta varia worker bees do not lay eggs even when living in queenless colonies, a condition that favors ovary development and oviposition in the majority of highly social bees. The permanent sterility of these worker bees was initially attributed to a failure in ovary morphogenesis and differentiation. Using transmission electron microscopy we found that at the beginning of the pupal phase the ovaries of F. varia workers are formed by four ovarioles, each of them composed of 1) a terminal filament at the apex of the ovarioles, containing juxtaposed and irregularly shaped cells, 2) a germarium with clusters of cystocytes and prefollicular cells showing long cytoplasmic projections that envelop the cystocyte clusters, 3) fusiform interfollicular and basal stalk precursor cells, and 4) globular, irregularly contoured basal cells with large nuclei. However, during the pupal phase an accentuated and progressive process of cell death takes place in the ovarioles. The dying cells are characterized by large membrane bodies, electron-dense apoptotic bodies, vacuoles, vesiculation, secondary lysosomes, enlarged rough endoplasmic reticulum cisternae, swollen mitochondria, pycnotic nuclei, masses of chromatin adjacent to the convoluted nuclear envelope, and nucleoli showing signs of fragmentation. Cell death continues in ovarioles even after the emergence of the workers. Once they become nurse bees, the ovaries have become transformed into a cell mass in which structurally organized ovarioles can no longer be identified. In F. varia workers, ovariole cell death most certainly is part of the program of caste differentiation.

GONADAL DAMAGE FROM CHEMOTHERAPY AND RADIOTHERAPY

Treatment with cytotoxic chemotherapy and radiotherapy is associated with significant gonadal damage in men and women. Alkylating agents such as cyclophosphamide and procarbazine are the most common agents implicated. The vast majority of men receiving procarbazine-containing regimens for the treatment of lymphomas become permanently infertile. Cisplatin-based chemotherapy for testicular cancer results in temporary azoospermia in most men, with a recovery of spermatogenesis in about 50% after 2 years and in 80% after 5 years. There is also evidence of Leydig cell impairment in a proportion of these men, although the clinical significance of this is not clear. The germinal epithelium is very sensitive to radiation-induced damage, with changes to spermatogonia occurring following as little as 0.1 Gy and permanent infertility after fractionated doses of 2 Gy and above. Cytotoxic-induced premature ovarian failure is age- and drug-dependent and ensues in approximately half of women treated with procarbazine-containing chemotherapy for lymphomas. High-dose chemotherapy, total body irradiation, and irradiation at an ovarian dose above 6 Gy usually result in permanent ovarian failure. The course of ovarian function after chemotherapy is variable, and late recovery occurs in some patients. Several methods of preserving gonadal function during potentially sterilizing treatment have been considered. Currently, sperm banking remains the only proven method in men, although hormonal manipulation to enhance the recovery of spermatogenesis and cryopreservation of testicular germ cells are possibilities for the future. Transposition of the ovaries to allow better shielding during radiotherapy is of use in some women, and the prospect of cryopreservation and reimplantation of ovarian tissue is promising.

The pregnant man—an oxymoron?

The desire to found a family is a gender neutral one. Pregnancy is not—in our culture it is considered to be an exclusively female activity. This study focuses on female to male transsexuals (FTMs) who chose to bear a child, while being conscious of their transsexual male identity, and who therefore transitioned shortly afterwards. Problems this group have to face include: finding a supportive environment, defining their individual perception of masculine identity and handling the organisational aspects of transitioning. These consist of dealing with therapists and or medical caregivers who are required to write or approve the necessary referrals for name change, hormones or surgeries. Additionally meeting the standards legally required for a name/gender change can be complicated as these frequently request permanent sterilisation or a non‐marital status. Several FTMs who transitioned either during or after pregnancy (a maximum of three years afterwards) have been interviewed, particularly in respect to the response of their social environment. The request of permanent sterility for FTMs who wish to change their gender legally is discussed from a feminist and human rights perspective and from the male self‐perception of the FTMs involved in the study.

Floral sex ratios, disease and seed set in dioecious Silene dioica

1 In the dioecious, perennial herb Silene dioica, the density of pollen donors in a population is determined by overall plant density, the sex ratio and the proportion of plants infected with the anther‐smut fungus Microbotryum violaceum, which results in permanent sterility of both male and female plants. 2 Pollinators (Bombus spp.) were found to prefer male flowers and to avoid diseased flowers. This may result in an overall lower visitation frequency and increased risk for pollen limitation in populations with a low density of males or a high incidence of disease. 3 Compared with open‐pollinated flowers, hand pollination resulted in a significant increase in the number of seeds produced per fruit in populations with an experimentally reduced proportion of males (25% and 50% male flowers) but not in a naturally male‐dominated population (75% male flowers). Seed production per plant was increased by hand pollination only in the most female‐dominated population. Because the floral sex ratio is often male‐biased, resources rather than pollen availability are likely to set the upper limit for total seed production per individual in most healthy populations of S. dioica. 4 There was a negative relationship between seed set and incidence of disease across 22 populations in both years of a field study. However, there was no consistent difference between the responses of highly diseased populations (incidence 30–56%) and populations with a low disease incidence (incidence 0–8%) to hand pollination. 5 In a greenhouse experiment with cloned hand‐pollinated females, the presence of spores on healthy flowers was found to reduce seed set significantly. In highly diseased populations, therefore, the frequent deposition of spores by flower visitors onto remaining healthy plants may decrease seed production below the potential level determined by resources or pollen availability.

Testicular atrophy in a mule deer population.

Monitoring mule deer (Odocoileus hemionus) on a former plutonium production site along the Columbia River at the Hanford Site, Washington (USA) revealed 27 (23%) of 116 adult males had unusually shaped, velvet-covered antlers and abnormally developed testicles. We captured 32 males to examine age-class differences and the ratio of affected to unaffected deer and determine whether affected testicles were atrophic or hypoplastic. We found testicular atrophy in most deer with velvet-covered antlers, primarily in animals older than 5 yr. Deer had marked to extreme stages of testicular atrophy, indicating permanent sterility. Decreased serum levels of testosterone and compensatory increased levels of luteininzing hormone and follicle stimulating hormone were detected in all affected males; thus, the gondopituitary hormonal pathway may have responded to abnormally low levels of testosterone in the affected animals. Brucella spp. antibodies in sera were not detected and 9 (90%) of 10 affected animals were seropositive for epizootic hemorrhagic disease virus (EHDV-2) and bluetongue virus (BTV-11) as compared to 12 (63%) of 19 unaffected animals; however, signs of other infectious diseases were not observed. Testicular degeneration generally exceeded that observed with nutritional disorders and poisons in domestic species. Also, severity of the atrophy and apparent lack of other affected tissues suggested that radiation may not be responsible. Testicular atrophy in mule deer has been reported elsewhere; however, neither prevalence has been as high nor or occurrence as well confined to a specific geographical area, as that observed at the Hanford Site. Furthermore, no physiological or age-related influences were described. Documenting the status of such variables and examining their relationships to this phenomenon is a crucial step in understanding the reproductive capacity of a wild deer population.

Can foxes be controlled by reducing their fertility?

A model based on data from research in New South Wales conducted by the Cooperative Research Centre for the Biological Control of Vertebrate Pest Populations suggests that the effectiveness of fertility control in reducing the abundance of foxes (Vulpes vulpes) can be strongly influenced by environmental variability. The model includes age-specific recruitment and survival as functions of resources indexed by rainfall. It is assumed that fertility control will affect only female foxes and that the use of a baiting regime to deliver a contraceptive agent will result in fixed proportional changes in pregnancy rates. By comparing the variability in the rate of increase of treated and untreated fox populations, the model predicts that: (i) frequent baiting, every one or two years, will be more effective than applications of baits at longer time intervals; (ii) the abundance of foxes will decline more rapidly, with higher levels of fertility control; (iii) infertility which lasts for only one breeding season is less effective than permanent sterility which allows for accumulation of sterile animals in the population; and (iv) highly variable results are likely to be the outcome of low-frequency baiting with an agent that produces only temporary infertility.

Infertility and subfertility in Norwegian women aged 40-42. Prevalence and risk factors.

There are few population estimates of the prevalence of infertility that also include some information about medical conditions and social classification of study objects. This is a study of 4034 out of a total of 5139 (78% of all invited) women in one county of Norway. All female inhabitants born 1950 to 1952 living in the county were invited to participate in a health screening. The screening comprised a clinical screening and two questionnaires; one about reproductive history and infertility. This survey found permanent primary infertility in 2.6% of the women. Subfertility, as at least one year's delay of pregnancy, was reported by 7.7%. A history of different reproductive problems was associated with impaired fertility. Thirty-two percent of primary infertile women had a history of PID, 13% had experienced amenorrhea and almost 40% reported premenstrual tension, compared with lower frequencies in women with normal fertility (11.0%, 3.3% and 29.4% respectively). Up to 10% of the female population may experience infertility at one stage in their reproductive career. Clinicians should pay special attention to women presenting any genital or reproductive disorder regarding risks for future fertility impairment.

Detection of the effects of phytoestrogens on sheep and cattle.

Cows and ewes fed estrogenic forage may suffer impaired ovarian function, often accompanied by reduced conception rates and increased embryonic loss. Males are relatively unaffected, but the mammary glands in females and castrate males may undergo hypertrophy of the duct epithelium, accompanied by secretion of clear or milky fluid. In cows, clinical signs resemble those associated with cystic ovaries. The infertility is temporary, normally resolving within 1 mo after removal from the estrogenic feed. However, ewes exposed to estrogen for prolonged periods may suffer a second form of infertility that is permanent, caused by developmental actions of estrogen during adult life. The cervix becomes defeminized and loses its ability to store spermatozoa, so conception rates are reduced, although ovarian function remains normal. Importantly, both temporary and permanent infertility in ewes often occur without observable signs and can be detected only by measurement of phytoestrogens in the diet, or measurement of their effects on the animal. Low background concentrations of dietary phytoestrogens are suggested to play an important role in prevention of disease in humans and laboratory rats, but subclinical effects of phytoestrogens in cattle have not yet been described. Effects of low concentrations of phytoestrogens on reproductive function in ruminants are likely to receive increasing attention.

Clomiphene citrate reduces procarbazine-induced sterility in a rat model

Chemotherapy with the cytotoxic drug procarbazine (PCB) causes permanent infertility in most male patients. Since many patients treated with this cytotoxic drug are of reproductive age, it is important to develop a method to protect spermatogenesis and fertility. It has been hypothesised that 'spermatogenic arrest' by pharmacological intervention may render the testes less susceptible to the effects of chemotherapy. The present study investigated whether recovery of fertility in a male rat model could be achieved by suppression of spermatogenesis with high doses of clomiphene citrate (CC) prior to PCB administration. It was demonstrated that young male rats treated with a combination of CC and PCB partially recovered spermatogenesis and achieved almost normal fertility. In contrast, animals treated with PCB alone exhibited abnormal spermatogenesis and remained infertile.

Organizational and activational effects of phytoestrogens on the reproductive tract of the ewe.

Ewes exposed to phytoestrogens may display two forms of infertility, categorized as temporary or permanent. Temporary infertility results from actions of estrogen that are similar to the activational effects of estrogen in most species of mammals. The permanent infertility results from changes to the cervix which are analogous to the organizational effects of estrogen reported in other species treated during organogenesis. However, in the ewe these effects may be produced after organogenesis by prolonged treatment during adult life. It has recently become apparent that the level of nutrition and metabolic hormones influence the degree of uterus-like histological change in the cervix produced by prolonged treatment with estrogen. It is hypothesized that, under some nutritional conditions, the hormonal milieu in adult ewes may simulate hormonal patterns that are normally experienced by fetal lambs in utero, thereby allowing the cervix of the adult ewe to give an organizational response to estrogen.

Infertility: Ultrastructure of human ovarian primordial follicles after combination chemotherapy for Hodgkin's disease

Ovarian damage, with consequent permanent infertility, is one of the more common side-effects which occurs during chemotherapeutic treatment of patients affected by Hodgkin's disease. This damage is morphologically represented by a marked loss of primordial and primary follicles. The administration of contraceptive drugs before starting chemotherapy enhances survival of a greater number of ovarian follicles, as revealed by morphometric analyses, nevertheless, total ovarian protection is not assured. This study evaluated the number and the morphology of ovarian follicles, by means of transmission electron microscopy, in patients with Hodgkin's disease treated with multi-drug chemotherapeutic protocols following the administration of medroxyprogesterone acetate. Ovarian biopsies were performed prior to any pharmacological treatment, after medroxyprogesterone therapy, and after this therapy plus chemotherapy. Particular attention was given to the ultrastructure of primordial follicles. After morphometric evaluation, primordial follicles were numerous in controls and medroxyprogesterone therapy (28.55 +/- 6.59/mm3 of ovarian cortex). After chemotherapy and medroxyprogesterone acetate, the number of follicles was slightly reduced (19.37 +/- 3.41/mm3 of ovarian cortex) in contrast to the dramatic loss usually observed when protection is not given, although more follicles were atretic. Medroxyprogesterone may protect follicles only from acute, toxic effects of chemotherapy, which dramatically reduce their number and lead to sterility. Nevertheless, the quality of follicles is still impaired, and many undergo atresia, resulting in a shortened fertility period.

Effects of prolonged exposure of ewes to oestrogenic pasture 1. Permanent flock infertility following long-term grazing of red clover (‘Grasslands Pawera’)-dominant pasture

Abstract Romney ewes grazed red clover (P) or mixed red clover/ryegrass (M) pastures for about 6 months/year until mating in Year 4 (P) or 5 (M) of a 6-year study. A further group grazed ryegrass/ white clover (C) pasture continuously throughout the study. At other times all animals grazed ryegrass/white clover pasture as one mob. Ewes grazing P pasture were consistently 3–6 kg heavier than ewes that grazed C pasture. Despite similar proportions of ewes being marked by the ram, and similar ovulation rates, during the first cycle of mating each year, ewes grazing P pastures consistently showed increased returns to service (+30%), increased barrenness (+30%), and fewer lambs born per ewe joined (-0.5) than ewes grazing C pasture. Differences persisted after ewes were removed from treatment pastures, indicating that infertility was likely to be permanent.

Development of uterus-like redifferentiation in the cervix of the ewe after exposure to estradiol-17 beta.

Prolonged treatment with estrogen causes the cervix of the ewe to redifferentiate to become more like uterus, and results in permanent infertility. Such permanent infertility has been observed only in ewes that have received two successive exposures to estrogen, raising the possibility that the initial exposure has a priming effect for subsequent treatment. In the study presented here, we examined whether any priming effects could be detected in the development of uterus-like histological changes in cervix of ewes given a single or two successive treatments with estradiol. Exposure to estradiol for 180 days resulted in stratified squamous hypertrophy of the cervical epithelium and also produced glandular hyperplasia, an increased proportion of lamina propria tissue in the endocervix, and fewer cervical folds. During the 30 days after treatment ceased, the epithelium returned to normal, while changes in cervical structure, as measured by reduced number of folds, became more marked. A second treatment with estradiol 180 days later produced a response similar to that after the first exposure, so it was not possible to identify any specific priming effect of the initial treatment with estrogen. However, treatment with estrogen established a process of cervical redifferentiation, and some aspects of this change appeared to be dependent on the withdrawal of estrogen.

Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin's lymphomas.

Treatment of lymphomas with combination chemotherapy with or without radiation therapy (XRT) can result in long-term or permanent azoospermia. Semen analyses of lymphoma patients were performed before, during, and after treatment with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo) chemotherapy. Some of the patients also received other drugs or radiation therapy. Although no patients were azoospermic before treatment, all were rendered azoospermic during treatment. Following the completion of treatment, the fraction of patients whose sperm counts recovered increased gradually over 5 years and plateaued by 7 years, with two thirds of the men achieving normospermic levels. Scattered gonadal radiation dose and cumulative cyclophosphamide dose were found to be independently significant determinants of recovery: the fraction of patients whose sperm counts recovered to 10 x 10(6)/mL were 83%, 47%, and 20% for those who received less than 9.5 g/m2 of cyclophosphamide, greater than 9.5 g/m2 of cyclophosphamide, and pelvic XRT, respectively. The inclusion of additional drugs and interferon alfa did not significantly affect the long-term recovery of spermatogenesis. Pelvic XRT and cumulative cyclophosphamide dosages greater than 9.5 g/m2 are associated with a high risk of permanent sterility in lymphoma patients treated with the CHOP-Bleo regimen.

Contraception and women's health.

More and more women all over the world are opting for fertility by choice not by chance. Contraceptive use has a tremendous impact on women's health. The ability to regulate and control fertility is a basic component of health, positively defined as a state of physical, mental and social well-being. Contraception is saving the lives of women around the world from the hazards of unwanted pregnancy. Optimal childbearing is also contributing to infant and child survival. Contraception has a complex relationship to sexually-transmitted diseases. Contraceptive safety is a major public health concern. The risk/benefit assessment will differ for different populations, for different individuals, and even for the same individual at different periods of life. The family planning movement started as a movement by women for women. Women's perspectives and women's concerns should guide the future of contraceptive research and development.

Sterilization of Workers from Pesticide Exposure: The Causes and Consequences of DBCP-Induced Damage in Costa Rica and beyond

Public health hazards from the use of agricultural pesticides have received increasing attention in developing as well as industrial nations. This article examines a remarkable case of massive sterilization of approximately 1,500 workers in Costa Rica, due to exposure to a toxic nematicide called DBCP 1,2-dibromo-3-chloropropane), applied in large commercial banana plantations. Although the product was used during the 1970s, sterile victims have continued to be diagnosed through the 1980s. The effects include psychological trauma as well as permanent infertility. The case has international repercussions because several hundred workers have filed law suits against the U.S.-based transnational DBCP manufacturers, and because DBCP use was continued during the 1980s in other developing nations. The author analyzes the causes behind this serious impairment. It is argued that the contributing factors include not only biomedical processes and technical dimensions (i.e., how DBCP was used), but most importantly, political-economic factors that explain how and why DBCP was used despite the severe hazard. The crucial determinants pertain to the dominance of short-term profit motives, and the control over information and technology by the manufacturers (who concealed early toxicological research evidence of the reproductive hazards) and by the managers of the banana producer-companies. This case well illustrates problems and injustices from labor exploitation and resource extraction from transnational agro-industries. The article concludes with a brief summary of policy implications from the case.

Fertility following cancer therapy

<h2>Abstract</h2> This article reviews the literature relating to fertility following cancer therapy. Normal fertility clearly relies on normal gonadal and normal sexual function. Consideration is given here to the possible effects of surgery, radiotherapy and chemotherapy on fertility. Surgical techniques have now been described which in selected patients may allow normal erectile and ejaculatory function in the male, where previously impotence was inevitable. Maintaining radiation doses to the testes and ovaries to a minimum will reduce the incidence of radiation-induced sterility and may allow recovery of gonadal function. It is clear that cytotoxic chemotherapy does not inevitably result in permanent sterility. Some regimens are more toxic in this respect than others, and reducing the number of courses may improve the chances of retaining fertility. Hormonal manipulations designed to protect the gonad against cytotoxic damage have thus far been unsuccessful in the clinical situation.

Permanent infertility in ewes exposed to plant oestrogens

In Australia, more than 1 million ewes have permanently damaged reproductive tracts because they have been grazed on oestrogenic pasture. These effects occur in the absence of classical clinical "clover disease". The lesions result from an "organisational" action of oestrogen, causing a mild sexual transdifferentiation to occur in ewes during adult life, with the main lesion being found in the cervix. Diagnosis of the problem depends primarily on detection of the pathological changes, rather than history or clinical signs. On average, affected flocks have around a 10% increase in non-pregnant ewes, but most farmers can achieve an acceptable lambing rate by increasing their management and feed inputs to produce more twin lambs. Agronomic approaches have been used in the past to combat "clover disease", but further progress with the present problem may depend on the development of animal-based solutions.