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PubMed1998

Mifepristone. Auxiliary therapeutic use in cancer and related disorders.

OBJECTIVE: To evaluate the efficacy of mifepristone, a potent antagonist of progesterone and glucorticoids, in the management of cancer and disorders related to reproduction. STUDY DESIGN: Reports describing clinical trials of mifepristone treatment of leiomyoma, breast cancer, endometriosis and meningioma were reviewed. Mifepristone is a potent antagonist of progesterone and glucocorticoids. It is an effective contraceptive and abortifacient and in addition has been used in the management of diseases associated with pregnancy and adrenal cortical function. Results of the clinical trials show that it has beneficial and palliative value in some cases. Mifepristone may be used as an adjuvant therapeutic agent in cases of unresectable meningioma and leiomyoma that are refractory to chemotherapy, endocrine treatment or irradiation. In extensive endometriosis, mifepristone is indicated for intractable pain, although its effect on the lesions will be minimal. In the management of unresectable and metastatic breast cancer, mifepristone may be considered after a course of chemotherapy and/or irradiation and only in combination with another agent. In Cushing's syndrome mifepristone may be used to treat the undesirable sequelae of excessive cortisol production-e.g., psychosis. It will have minimal or no effect on the lesions of the adrenal or pituitary. The adverse effects of the long-term use of mifepristone are slight to moderate and reflect antiglucocorticoid effects. During treatment with mifepristone one should be aware of the possibility that the patient will develop Addisonian-like syndrome in the face of elevated blood ACTH and cortisol levels. RESULTS: Leiomyoma treated with 25 or 50 mg/d of mifepristone underwent a 25-49% reduction in tumor size. Treatment of endometriosis with a daily dose of 50 or 100 mg of mifepristone alleviated pelvic pain and uterine cramps and induced about 55% regression of the lesions. Treatment of metastatic breast cancer with 200 or 400 mg/d of mifepristone resulted in a partial response. Unresectable meningioma treated with 200 or 400 mg/d of mifepristone produced objective improvement in about 25% of subjects. CONCLUSION: Mifepristone is beneficial as adjuvant treatment in the management of unresectable, hormone-dependent tumors and disorders of the female reproductive system that are refractory to chemotherapy and irradiation.

Adult↗
PubMed2000

A risk factor for female fertility and pregnancy: celiac disease.

Celiac disease is a genetically-based intolerance to gluten. In the past, celiac disease has been considered a rare disease of infancy characterized by chronic diarrhea and delayed growth. Besides the overt enteropathy, there are many other forms which appear later in life; target organs are not limited to the gut, but include liver, thyroid, skin and reproductive tract. It is now recognized that celiac disease is a relatively frequent disorder; the overall prevalence is at least 1:300 in Western Europe. Celiac disease may impair the reproductive life of affected women, eliciting delayed puberty, infertility, amenorrhea and precocious menopause. Clinical and epidemiological studies show that female patients with celiac disease are at higher risk of spontaneous abortions, low birth weight of the newborn and reduced duration of lactation. No adequate studies are available on the rate of birth defects in the progeny of affected women; however, celiac disease induces malabsorption and deficiency of factors essential for organogenesis, e.g. iron, folic acid and vitamin K. The overall evidence suggests that celiac disease patients can be a group particularly susceptible to reproductive toxicants; however, the pathogenesis of celiac disease-related reproductive disorders still awaits clarification. At present, like the other pathologies associated with celiac disease, the possible prevention or treatment of reproductive effects can only be achieved through a life-long maintenance of a gluten-free diet.

Adult↗
PubMed1999

Effect of vibrations on male reproductive system and function.

From data in the literature, the potential risk of mechanical vibrations on reproduction in experimental, clinical and epidemiological studies (in experimental animals, men occupied in transport and industry), as well as the influence on sexuality are summarised. Results of the authors own experimental and clinical studies on the influence of the vibration on the male reproductive system are also presented. In male rats, decreased sperm counts, spermatogenesis index and size of testes, changed character of their motion, chronic venous stagnation and dystrophic alterations in tubuli contorti, changed ScDH, ATP-ase, LDH and GL-6-PDH activity, germ cells structural damages were observed. Workers exposed to vibrations had an increased prevalence of oligozoospermia, asthenozoospermia and teratozoospermia. Sexual disorders are also observed. The authors suggest that reproductive disorders should be included in the list of non-specific effects of vibrations. The detected changes justify further investigations and development of mathematical models for early detection and prognosis of the unfavourable effect on male reproductive function.

Animals↗
PubMed2006

Hypertensive disorders of pregnancy are an evolutionary adaptation to mitigate the reproductive consequences of the human physique.

The aetiology of hypertensive disorders of pregnancy remains unknown, despite over 30 years of research. The prevalence and natural history of these disorders and the lack of progress in identifying a cause calls for a radical new approach. It is hypothesised that these disorders arise as a consequence of abnormal maternal regulatory mechanisms. The evolution of the physical characteristics unique to humans (bi-pedal gait and a large brain) resulted in a narrow pelvis and a large head. Such a physique is not conducive to viviparity and caused difficult, prolonged and obstructed labour with post-partum haemorrhage--the commonest causes of maternal mortality in the absence of modern medical care. In such circumstances, up to 6.5% of pregnant women will die as a direct consequence of pregnancy, mainly as a result of obstructed labour and haemorrhage. The death toll would have been much higher over millions of years of evolution. These conditions exerted significant adaptive and evolutionary pressure on our species. The adaptations necessary to mitigate the reproductive consequences of the human physique include activation of the coagulation system to reduce post-partum haemorrhage, increased blood pressure to peak after delivery and maintain cerebral perfusion in the face of post-partum blood loss and restriction of fetal growth to prevent obstructed labour. These adaptations must be regulated to guarantee their occurrence but limit their extent to prevent disease. Evidence for blood pressure regulation during pregnancy and a proposed mechanism to achieve this are presented. Regulation requires a redundant feto-placental signal and a single tightly controlled regulator. To guarantee that blood pressure rises, the feto-placental signal is predicted to be conveyed by several different molecules and to be produced in excess in all pregnancies. Normality is then maintained by a single tightly controlled regulator. This model predicts that the feto-placental factors that cause a rise in maternal blood pressure are multiple and produced in disease-causing concentrations in all pregnancies. Disease arises as a consequence of abnormalities in the maternal regulatory mechanism as occurs in say gestational diabetes mellitus. The search for a placental cause for pre-eclampsia is therefore futile. Research should focus on normal pregnancy and the identification of the factor that regulates maternal blood pressure in the second half of pregnancy. This factor will cause hypotension and prevent endothelial activation and have a role analogous to insulin in the regulation of glycaemia and the development of gestational diabetes mellitus.

Acclimatization↗
PubMed2006

The progesterone metabolite allopregnanolone potentiates GABA(A) receptor-mediated inhibition of 5-HT neuronal activity.

The dorsal raphe nucleus (DRN) is the origin of much of the 5-HT innervation of the forebrain. The activity of DRN 5-HT neurons is regulated by a number of receptors including GABA(A) and 5-HT(1A) inhibitory receptors and by excitatory alpha(1)-adrenoceptors. Using in vitro electrophysiological recording we investigated the action of progesterone and its metabolite, allopregnanolone on receptor-mediated responses of DRN 5-HT neurons. Neither allopregnanolone nor progesterone affected the alpha(1)-adrenoceptor agonist-induced firing. Allopregnanolone also had no effect on the inhibitory response to 5-HT. However, allopregnanolone significantly potentiated the inhibitory responses to GABA(A) receptor agonists. Progesterone did not enhance GABA(A) receptor-meditated inhibitory responses. Thus, the neuroactive metabolite of progesterone, allopregnanolone, has the ability to cause potentiation of GABA(A)-mediated inhibition of DRN 5-HT neurons. This effect on 5-HT neurotransmission may have relevance for mood disorders commonly associated with reproductive hormone events, such as premenstrual dysphoric disorder and postpartum depression.

Action Potentials↗
PubMedDate not supplied

Internal medicine and reproduction: male hypogonadism.

Awareness of the complex relation linking reproductive function and other major organ systems has been increasing only recently. We have tried to delineate some recent advances in our knowledge of male reproductive function and its disorders as they relate to Internal Medicine. The regulation of Gn-RH secretion and the influence of Gn-RH on gonadotropin secretion are among the most interesting aspects of hypothalamic-pituitary function. The pulsatile pattern of LH secretion is of particular interest in relation to the influence of gonadotropin secretory pattern on testis response. In this regard oligozoospermia with elevated FSH levels and decreased frequency of LH pulses has been identified. Sertoli cells play an essential role in the control of spermatogenesis. We investigated some features of human Sertoli cell function in vitro. These cells secrete transferrin and ABP, and hABP has an affinity for DHT which is different from that of liver-produced SHBG. Seminal transferrin is closely linked to spermatogenesis in oligozoospermia as well as in azoospermia due to damaged spermatogenesis. As a third point of interest paracrine control of testis function, and especially the paracrine role of endogenous opiates and several growth factors are described. LH pulsatility was studied in several medical and endocrine disorders to investigate their impact on male reproductive function. An altered pattern of LH secretion was found in most of the diseases investigated, and in some instances there were hints of hypothalamic involvement. Finally the negative influence on male reproductive function of several drugs, commonly used in the practice of internal medicine is stressed.

Blood-Testis Barrier↗
PubMed2001

[Influence of chemicals on female reproduction].

Studying female reproductive health in city with developed chemical industry, the authors revealed significant difference in character and incidence of disorders between the chemical workers and general population. Calculated dependence of some reproductive disorders on values of chemicals in the air helps to forecast the risk degree.

Adult↗
PubMed2007

[Reproduction and psyche].

Mental health and mental disorders can have a close connection to reproduction, especially for women but also for men. The most frequent disorders or problems are described, i.e., mental problems during pregnancy and after delivery, during the menstrual cycle and around menopause. Possible consequences of miscarriage, stillbirth and induced abortion are presented as well as the special problem of a wish for a child in mentally ill women and their treatment during pregnancy.

Female↗
PubMed1996

Prevalence of antibodies to lipid A in Danish cattle.

A cross-sectional study was performed on the occurrence of IgG antibodies to lipid A of the Gram-negative bacterial lipopolysaccharide (LPS, endotoxin) on serum of 2272 cattle distributed on 19 Danish dairy herds. The relationship between the concentration of antibodies to lipid A (ALI) and age, herd, pregnancy rate and occurrence of mastitis, bovine virus diarrhoea (BVD), reproductive and digestive disorders, diarrhoea, pneumonia, foot disorders, various infections and traumatic udder lesions was investigated. ALI generally was low in calves and increased during their first 1.5 years of life to a steady state, which could be altered by the occurrence of disease. There were significant differences in the mean ALI among the herds (P < 0.001). High ALI was associated with a low herd pregnancy rate, to preceding occurrence of mastitis (P < 0.048), BVD (P < 0.01), reproduction diseases (P < 0.041) and digestion disorders (P < 0.064) in animals older than 2 years. The calf mortality rate was not associated to ALI and there was no correlation between the ALI in calves and their dams. The occurrence of high ALI levels on a herd basis may be an indication of increased challenge or enhanced immunological defense to Gram-negative bacteria or endotoxin.

Aging↗
PubMed2001

Time perception and reproduction in young adults with attention deficit hyperactivity disorder.

Adults with attention deficit hyperactivity disorder (ADHD; n = 104) were compared with a control group (n = 64) on time estimation and reproduction tasks. Results were unaffected by ADHD subtype or gender. The ADHD group provided larger time estimations than the control group, particularly at long intervals. This became nonsignificant after controlling for IQ. The ADHD group made shorter reproductions than did the control group (15- and 60-s intervals) and greater reproduction errors (12-, 45-, 60-s durations). These differences remained after controlling for IQ and comorbid oppositional defiant disorder, depression, and anxiety. Only the level of anxiety contributed to errors (at 12-s duration) beyond the level of ADHD. Results extended findings on time perception in ADHD children to adults and ruled out comorbidity as the basis of the errors.

Adult↗
PubMed1987

Effects of the sex-linked prenatal lethal gene tortoise (Moto) on reproduction and growth in the mouse.

The sex-linked prenatally lethal gene tortoise (Moto), an animal model for the human disorder known as Menkes' Kinky Hair Syndrome (MKHS), was studied in the mouse (Mus musculus). The genetic effects upon reproductive performance, birth weight, preweaning growth, and mortality were evaluated to characterize the debilitating effects of the disorder. Reproductive performance of mice were evaluated in two mating types (dam X sire), mutant female (To/+) X normal male (+/Y) and normal female (+/+) X normal male (+/Y). Litter size was reduced in the To/+ X +/Y mating type as expected due to the death of To/Y offspring in utero. Adjusted birth weight of To/+ and +/Y offspring were identical, and both were greater (P less than 0.05) than +/+ offspring. Within one day, however, the To/+ littermates were smaller (P less than 0.05) than +/+ and +/Y and remained consistently inferior in growth through day 30. Normal females and normal males were similar (P greater than 0.05) in growth from day 1 through day 21. Thereafter, +/Y mice were consistently heavier (P less than 0.05) than +/+ mice through day 30. The To/+ genotype had the greatest (13.8%) preweaning mortality rate; +/+ and +/Y genotypes were comparable as were overall comparisons between parity 1 and 2. It is apparent from this study that the copper deficiency and lethality occurring in the progeny of mottled mice were primarily the result of the gene actions in the heterozygote animals. Progression of the disorder may be prevented by experimental determination of both the timing and targeting of in utero therapy in mottled mice and MKHS fetuses.

Animals↗
PubMed2006

Advancing parity is associated with high milk production at the cost of body condition and increased periparturient disorders in dairy herds.

The objectives of this study were to determine the effects of parity on milk production, body condition change, periparturient health, and culling in Korean dairy herds. The data utilized included; milk yield, body condition score, cow parity, calving condition, periparturient disorders, culling, and reproductive status, which were recorded from 1290 calvings in eight dairy herds. The mean milk yield in cows over 305 days increased with increasing parity (p < 0.01). Cows with parities of 3, 4, and 5 or higher lost more body condition than those with a parity of 1 during month 1 of lactation (p < 0.01), and body condition recovery by cows with parities of 4 and 5 or higher was slower (p < 0.01) than recovery by cows with parities of 1, 2, or 3 until month 3 of lactation. The risk of retained placenta, metabolic disorder, and endometritis also increased with advancing parity (p < 0.05). Moreover, the incidence of ovarian cysts was lower in cows with a parity of one than in cows with greater parities (p < 0.01). Culling rate due to reproductive failure also increased with advancing parity (p < 0.01). These results suggest that parity increases milk yield, body condition loss during early lactation, the risk of periparturient disorders, and culling due to reproductive failure in dairy herds.

Animals↗
PubMed2001

[Reproductive medicine from childhood to adulthood].

Modern era brought new diagnostic and therapeutic methods to endocrinology and changed the approach to many diseases and developmental disorders. Explosion of new findings brought about the possibility of examinations on subcellular level. Possibility to study structure and function of various genes is not any more the futurology. However, still in medicine romain a roas which are considered as less important. It is usually assumed that questions of fertility will be dealt by the specialist for adults. We suppose that the given problems should be well advised by an interdisciplinary co-operating team in the paediatric patients already. However, it should be recognised that some reproduction disorders have their origin in the early age. The aim of this paper is to give an overview on endocrine disorders in relation to reproduction impairments and to outline possibilities of co-operation between different specialist treating patients from childhood trough adulthood.

Adult↗
PubMed1993

The pineal gland in human beings: relevance to pediatrics.

Several facts suggest that the pineal gland must have a significant role in human beings: the presence of melatonin secretion from infancy to old age; a circadian secretory pattern similar to that found in animal species in which this gland has well-defined functions; its responsiveness to light; and the presence of melatonin receptors in the hypothalamus. Despite the importance of the pineal gland and melatonin in the reproductive activity of all nonprimate vertebrate species studied, the relationship of melatonin secretion to the activity of the hypothalamic-pituitary-gonadal axis in human beings remains presumptive. Some data suggest a possible pineal-reproductive connection throughout the human lifespan, but new research approaches are needed for a better definition of this connection during normal development and in disorders of the reproductive axis. In addition, recent studies that have applied strictly defined techniques to unravel the masking effects of various behavioral and environmental factors suggest that the pineal gland and melatonin have a fundamental role in the regulation of the human biologic clock. Melatonin concentrations in blood or urine may become a useful marker of the circadian rhythm in disorders of rhythms. Moreover, administration of melatonin in physiologic or pharmacologic doses may have an important application in suppression of the hypothalamic-pituitary-gonadal axis as a contraceptive, and in therapy for disorders of biologic rhythms. Among the latter, of particular interest to the pediatric population will be the potential application of melatonin treatment in establishing or reestablishing circadian rhythms in infants and children maintained for long periods under artificial light conditions, as encountered in intensive care units, and in the treatment of sleep and other rhythm disorders associated with developmental delay or blindness. Further research and approval by the U.S. Food and Drug Administration will be required before these applications will be available to the practicing pediatrician. The identification of melatonin receptors in the human hypothalamic fetal and adult tissues and the development of potent melatonin agonists and antagonists have paved the way for new research approaches that are needed to further investigate this intriguing, long-forgotten gland in human beings.

Humans↗
PubMed2000

Simulated effects on dairy cattle health of extending the voluntary waiting period with recombinant bovine somatotropin.

We simulated the effect of extending the voluntary wait period by 100 days on disorder-frequency measures that were based on cow-years (from lactations completed during the 4-year simulation horizon), metric tons of milk yield, and lactational incidence risks. A dynamic stochastic discrete-event simulation model that focuses on clinical and subclinical intramammary infections (IMI), plus clinical metabolic (left-displaced abomasum, ketosis, milk fever) and reproductive (cystic ovarian disease, dystocia, retained placenta, twinning, uterine infection) disorders in dairy herds was used. Although the voluntary wait period was increased by 100 days (50 vs. 150), the predicted difference in simulated days to conception was only 89 days for the extended voluntary wait-period group (which we attributed to higher fertility later in lactation). Herds that had a voluntary wait period of 150 days (compared to the control herds' voluntary wait period of 50 days) were predicted to have significantly lower rates of metabolic and reproductive disorders and clinical mastitis on both cow-year and milk-yield bases. Simulated control herds, on average, produced 8539 kg of milk in an average lactation of 325 days and simulated herds with a 150-day voluntary wait period 10893 kg of milk in an average lactation of 409 days. There was a significantly lower predicted rate and risk of culling for reproductive failure in the extended voluntary wait period group. The predicted lactational incidence risks for subclinical IMI were 18% higher for the extended voluntary wait period group - but extending the voluntary wait period by 100 days was predicted not to increase the risk of any of the other 10 disorders.

Algorithms↗
PubMed2002

Effects of butyltins on human 5alpha-reductase type 1 and type 2 activity.

Butyltins are widely used biocides and accumulate in the food chain. Tributyltin is an imposex-inducing endocrine disrupter in animals. Imposex is characterized by the development of additional male sex organs on females. In a previous study, we identified tributyltin as an inhibitor of human cytochrom P450 aromatase activity. The present work focuses on the impact of butyltins on human androgen metabolism. Activation of androgens is mediated by two human 5alpha-reductase isoenzymes. 5alpha-Reductase type 1 was completely inhibited by tributyltin chloride (IC50=19.9 microM) and dibutyltin dichloride (IC50=32.9 microM), whereas 5alpha-reductase type 2 was only inhibited by tributyltin chloride (IC50=10.8 microM). Both isoenzymes were not affected by tetrabutyltin or monobutyltin indicating that at least two butyl groups bound to the positively charged Sn are required for the interaction of butyltins with the enzymes. Tributyltin inhibited 5alpha-reductase type 1 competitively whereas an irreversible inhibition was evident for the type 2 isoenzyme. In contrast to the distinct effects on 5alpha-reductases, reductive brain 17beta-hydroxysteroid dehydrogenase activity was not inhibited by any butyltin. Insufficient activation of androgens is responsible for developmental disorders of the male reproductive system such as hypospadias. At pharmacologic levels butyltins might contribute to the onset of developmental disorders of the male reproductive system. At present, however, it is unknown whether these levels are reached after acute or chronic exposure to butyltins.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Melatonin in pathogenesis and therapy of cancer.

Melatonin is a neuroendocrine hormone secreted by the pineal gland to transduce the body's circadian rhythms. An internal 24 hour time keeping system (biological clock) regulated by melatonin, controls the sleep-wake cycle. Melatonin production is a highly conserved evolutionary phenomenon. The indole hormone is synthesized in the pinealocytes derived from photoreceptors. Altered patterns and/or levels of melatonin secretion have been reported to coincide with sleep disorders, jetlag, depression, stress, reproductive activities, some forms of cancer and immunological disorders. Lately, the physiological and pathological role of melatonin has become a priority area of investigation, particularly in breast cancer, melanoma, colon cancer, lung cancer and leukemia. According to the 'melatonin hypothesis' of cancer, the exposure to light at night (LAN) and anthropogenic electric and magnetic fields (EMFs) is related to the increased incidence of breast cancer and childhood leukaemia via melatonin disruption. Melatonin's hypothermic, antioxidant and free radical scavenging properties, attribute it to an immunomodulator and an oncostatic agent as well. Many clinical studies have envisaged the potential therapeutic role of melatonin in various pathophysiological disorders, particularly cancer. A substantial reduction in risk of death and low adverse effects were reported from various randomized controlled trials of melatonin treatment in cancer patients. This review summarizes the physiological significance of melatonin and its potential role in cancer therapy. Furthermore, the article focuses on melatonin hypothesis to represent the cause-effect relationship of the three aspects: EMF, LAN and cancer.

Humans↗