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Query: UMLS:C0021359 (infertility)
 26,075 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This updated literature review on heterosteroids and drug research has information on chemical structure, pharmacology, and effects. It first discusses the anti-inflammatory heterosteroids, such as mometasone furoate and cortivazol. It also covers heterosteroidal antimineralocorticoids and anabolic hetero derivatives. The review discusses at length the 19-norsteroid, mifepristone (RU-486), which exhibits antiprogestational activity and is being used for fertility control in women. It also has antiglucocorticoid activity and shows promise as a treatment of diseases characterized by muscle atrophy. In vitro studies indicate that mifepristone inhibits growth of breast cancer cell lines and of endometrial cancer cell lines. It has already exhibited growth inhibitory effects in some breast cancer patients. Discussions of mifepristone's pharmacokinetics and structural modifications of mifepristone follow. Danazol is an antigonadotropin and is used to treat endometriosis, benign breast disease, precocious puberty, hereditary angioneurotic edema, menorrhagia, some types of infertility, and gynecomastia. Danazol effects considerable changes in lipid metabolism. Other hormonal, antihormonal, and/or antifertility heterosteroids and/or aspects include androgen antagonists (e.g., cyproterone acetate), estrogen activity, antiestrogens, STS-557, and oximinosteroids. Heterosteroidal inhibitors of steroid hormone biosynthesis discussed are aromatase inhibitors, 5 alpha-reductase inhibitors, and 3 beta-hydroxysteroid dehydrogenase inhibitors (trilostane, epostane, and azastene). Heterosteroids affect the cardiovascular system, including the cardiac glycosides, antiarrhythmic agents, and antilipemic agents. Some heterosteroids affect central nervous system activity (e.g., RU-5135 causes convulsions in rodents). Pancuronium analogues and chandonium and analogues are neuromuscular blocking azasteroids. In addition to danazol and RU-486, several other antineoplastic heterosteroids exist (e.g., estramustine phosphate sodium, a prostate cancer drug).
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PMID:Heterosteroids and drug research. 184 48

GRF promotes follicular maturation and ovulation when administered with FSH in the treatment of infertility. Such actions could be mediated by stimulation of GH secretion and insulin-like growth factor I production, but the known actions of the structurally related hormone, vasoactive intestinal peptide (VIP), on granulosa cell function suggested that GRF may also act directly on the ovary to stimulate follicular development. Radioligand binding and activation studies, performed in granulosa cells from immature estrogen-treated rats, revealed a common receptor for VIP and rat (r) GRF in the ovary. Specific binding of [125I]VIP to granulosa cells was saturable and dependent on time and temperature. The relative potencies of VIP-related peptides for inhibition of radioligand binding were: VIP greater than rGRF greater than peptide histidine isoleucinamide greater than [His1,Nle27] human GRF(1-32)NH2 greater than secretin. In binding studies with the potent GRF agonist, [125I] [His1,Nle27]GRF(1-32)NH2, relative potencies were: rGRF(1-43)OH greater than [His1,Nle27]human GRF(1-32)NH2 greater than VIP greater than peptide histidine isoleucinamide greater than secretin. Glucagon and gastric inhibitory peptide, other peptides of the glucagon superfamily, and unrelated peptides including CRF and beta-endorphin, did not inhibit binding of either radioligand to ovarian receptors. In cultured granulosa cells, rGRF and VIP stimulated cAMP formation, consistent with coupling of their receptors to the adenylate cyclase system, and potentiated FSH-induced cAMP production. Both peptides also amplified FSH-induced progesterone biosynthesis, aromatase activity, and LH receptor formation. These observations demonstrate that rGRF is a potent cAMP-mediated agonist in the rat ovary and acts on a common VIP/GRF receptor in maturing granulosa cells. It is likely that the potentiating effect of administered GRF on gonadotropin-stimulated follicular development in vivo is in part mediated by direct actions of the peptide on the VIP/GRF receptor. Also, since GRF is present in the gonads, it is possible that the locally-produced peptide promotes follicular maturation by paracrine modulation of the stimulatory action of FSH on granulosa cell function.
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PMID:Receptor-mediated actions of growth hormone releasing factor on granulosa cell differentiation. 217 7

Bioactive FSH and immunoreactive FSH were determined in 193 infertile men and in 23 men with proven fertility using the Sertoli cell aromatase bioassay for bioactive FSH measurement and a two-site fluoroimmunoassay for immunoreactive FSH measurement. Overall bioactive and immunoreactive FSH levels correlated well (r = 0.74, p less than 0.001) but were significantly different from fertile men (bioactive FSH: 6.2 +/- 0.3 U/l; immunoreactive FSH: 4.1 +/- 0.4 U/l) in patients with Klinefelter's syndrome (24.1 +/- 6.1; 26.9 +/- 3.0), non-obstructive azoospermia (25.1 +/- 4.3; 22.2 +/- 4.0), maldescended testes (12.5 +/- 4.6; 14.6 +/- 1.6), and patients with severe oligozoospermia (11.9 +/- 1.2; 11.2 +/- 1.0). Infertile men with moderate oligozoospermia (8.9 +/- 1.5; 8.0 +/- 1.1) and normal sperm counts (9.6 +/- 1.1; 7.6 +/- 1.0) had insignificantly elevated bioactive FSH and immunoreactive FSH levels. Bioactive to immunoreactive FSH ratios were significantly reduced in all patient groups except for patients with normal sperm counts when compared with fertile men. A considerable number of patients exhibited elevated immunoreactive FSH concomitant with normal bioactive FSH levels. We conclude that 1. determination of immunoreactive FSH suffices for classification of patients; 2. bioactive to immunoreactive FSH ratios are reduced in infertile men; 3. some men might secrete immunoreactive FSH with reduced bioactivity.
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PMID:Diagnostic value of bioactive FSH in male infertility. 251 43

Subcutaneous treatment of immature male rats with an estrogen precursor, 19-hydroxy-testosterone (19-OHT), at a daily dose of 1 mg/animal for 14 days leads to a significant decrease in the weight of testis, ventral prostate and seminal vesicle. The peripheral levels of LH are lowered. Testicular histology indicates that the effects of 19-OHT are very similar to the known of effect induced by estradiol-17 beta. 19OHT induces a marked impairment of spermato- and spermiogenesis. The maturation division is completely inhibited. The effect of 19-OHT on spermatogenesis is partially reversed by concomitant administration of an aromatase inhibitor (4-acetoxy-4-androstene-3.17-dione, (4-AA] at a dose of 1 mg/animal/day s.c. Meiotic activity is restored, and the weights of genital organs and the serum LH values increase. 4-AA alone has no appreciable effect on the parameters examined in this study. The present results suggest that specific inhibitors of estrogen biosynthesis might not only be useful to investigate the patho-physiological role of estrogens on spermatogenesis, but also be suitable to some extent for the treatment of estrogen-induced infertility in men suffering from idiopathic oligozoospermia.
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PMID:Influence of an aromatase inhibitor (4-acetoxy-4-androstene-3,17-dione) on experimentally induced impairment of spermatogenesis in immature rats. 261 98

The hypothesis that increased estradiol production may be the cause of impaired spermatogenesis in infertile men with idiopathic oligozoospermia was tested by administering the aromatase inhibitor, testolactone, and by assessing its effects on sperm output and fertility. Our study was a randomized, placebo-controlled double-blind crossover trial. Subjects (n = 25) with infertility due to unexplained oligozoospermia were given testolactone (2 g/day) or placebo for 8 months followed by crossover to the other treatment for an additional 8 months. Total estradiol and testosterone levels during testolactone exposure did not change from basal and placebo values. However, sex hormone-binding globulin binding capacity consistently decreased (30%, p less than 0.01) and free testosterone levels increased (36%, p less than 0.01). Free estradiol values increased but not significantly. Additionally, LH and FSH serum levels increased by 15% and 20%, respectively (p less than 0.05), and 17 alpha-hydroxyprogesterone values increased by 90% (p less than 0.05) during drug administration. Sperm output and semen quality remained unchanged during either testolactone or placebo treatment, and no pregnancies occurred during the 16-month study. These data suggest that chronic administration of testolactone at this dose fails to maintain aromatase inhibition despite depression of 17,20-desmolase activity with elevated 17 alpha-hydroxyprogesterone and depressed SHBG binding capacity with elevation of free testosterone. Testolactone is not efficacious in the treatment of idiopathic oligozoospermic infertility.
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PMID:Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover. 266

The present review describes and discusses published results on growth and hormonal responsiveness of human endometrial stromal cells in culture. The proliferative potential of serially subcultured cells, that is, the number of cell doublings before cells enter mitotic senescence and cease to divide, was unusually high in stromal cells from several endometrial specimens, a property that may reflect the unique proliferative capacity of human endometrium when compared to other adult tissues. Fluorescent visualization of microfilaments revealed distinct age-related changes in the distribution of cytoskeletal fibers. Addition of ovarian steroids to the culture medium of stromal cells resulted in significant morphologic changes. From comparative studies using different culture media it became evident that medium components remarkably influenced cell morphology during early culture periods in an irreversible manner. Cultured stromal cells yielded interesting results in experiments designed to define the role of polyamines in growth regulation. Proliferation was greatly inhibited when polyamine levels were reduced by specific inhibition of ornithine decarboxylase, the first and rate limiting enzyme in polyamine synthesis which produces putrescine by catalytic conversion from ornithine. The antiproliferative effects were reversed by addition of putrescine to the culture medium. These results clearly establish a causal link between polyamine depletion and growth deficiencies and reveal an essential function of polyamines in stromal cell proliferation. Hormonally regulated parameters in cultured stromal cells include aromatase activity, pregnancy-associated plasma protein-A, 51K secreted protein, prolactin and laminin. The hormonally regulated production of prolactin and laminin, both considered markers of decidualization, together with morphologic changes of stromal cells to decidual-like cells, strongly suggest that human endometrial stromal cells, when subjected to appropriate hormonal stimulation, are capable of differentiating into decidual cells in culture. Cultured stromal cells therefore offer a unique opportunity to examine the complex changes in gene expression associated with decidualization. In addition, in vitro decidualization may prove to be an effective diagnostic tool in certain cases of infertility. Finally, decidualization of cultured stromal cells represents a relevant end point for testing compounds of potential clinical importance, such as synthetic progestins or antifertility drugs.
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PMID:Growth and hormonal responsiveness of human endometrial stromal cells in culture. 297 97

Efforts to develop a novel class of nonsteroidal aromatase inhibitors began with the discovery that the infertility in male rats exposed to high levels of the agricultural fungicide, fenarimol (alpha-(2-chlorophenyl)-alpha-(4-chlorophenyl)-5-pyrimidine-methanol), was attributable to the inhibition of aromatase activity within the central nervous system during the critical neonatal period. Although fenarimol was not particularly potent in inhibiting rat ovarian microsome aromatase activity in vitro (50% inhibition (IC50) = 4.1 microM). Subsequent testing of a number of analogues led to the identification of LY56110 (alpha,alpha-bis(4-chlorophenyl)-5-methylpyrimidine) which exhibited an IC50 of 29 nM. LY56110 was orally active, blocking the testosterone-induced increase of uterine weight and ovarian estrogen biosynthesis in immature female rats. In rats with established DMBA-induced mammary carcinoma, complete tumor regression was observed in 80% of the animals. Development of LY56110 was, however, stopped because of its effects on hepatic microsomal enzymes and an unacceptably long half-life. Structural modifications resulted in the development of the indenopyrimidines. LY113174 (8-chloro-5-(4-chlorophenyl)-5H-indeno less than 1, 2D greater than pyrimidine) was highly effective in vitro (IC50 = 24 nM) and in vivo but was far less potent than LY56110 with respect to induction of hepatic microsomal enzymes. LY113174 exhibited an acceptable biological half-life and had no effect on cholesterol side-chain cleavage. The indenopyrimidines appear to be a novel class of nonsteroidal aromatase inhibitors which may prove useful in the treatment of estrogen-dependent diseases.
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PMID:Discovery and development of a novel class of nonsteroidal aromatase inhibitors. 350 60

Fenarimol (alpha-(2-chlorophenyl)-alpha(4-chlorophenyl)-5-pyrimidine-methanol), a pyrimidine carbinol agricultural fungicide, was previously reported to cause a dose-related decrease in fertility in rats (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399). Based on the results of a number of reproduction studies (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399), the infertility appeared to be associated with an impairment of male sexual behavior. When [14C]fenarimol was administered to the dam, high concentrations of radioactivity were observed in the neonatal hypothalamus, which functions in the development and subsequent expression of male sexual behavior. In the present studies fenarimol exhibited neither antiandrogenic nor antiestrogenic activities. The compound did, however, prevent the increase in nuclear estrogen receptors in the brain which normally occurs in the male during the early postnatal period. These results suggested that fenarimol might be acting to inhibit estrogen biosynthesis (via the aromatase enzyme complex) within the central nervous system. [3H]Testosterone was administered to neonatal rats, and the tritiated metabolites were isolated. Testosterone and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) concentrations were similar in all treatment groups. Tritiated estrogens were detected in the brain cell nuclei from control neonates but not in neonates exposed to fenarimol. Fenarimol was also observed to inhibit rat ovarian aromatase activity in vitro. These data indicate that the decrease in male sexual behavior and the infertility associated with exposure to fenarimol were, most likely, due to inhibition of aromatase activity within the central nervous system.
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PMID:Inhibition of central nervous system aromatase activity: a mechanism for fenarimol-induced infertility in the male rat. 367 23

The enzymatic method for urinary estrogens determination from Nicolas et al. has become a useful tool for the management of infertility problems. It can be used for: investigation of ovarian by establishing the urinary estrogens profile during menstrual cycle, useful to: understand anomalies of the spontaneous cycle, explain some therapeutic failures during IVF attempts or artificial inseminations (AID or AIC); prediction of failures during IVF attempts during spontaneous cycles, and monitoring ovarian response during stimulated cycles in order to determine the trigger with hCG; monitoring ovulation during induction of ovulation in anovulatory patients stimulated with various drugs (clomiphene citrate, pure FSH combination of FSH and LH, GnRH ou analogs...) under various conditions of prescription and administration (oral, IM, intermittent pulsatile administration with portable pump with or without hypophyseal down regulation). This technique allows also exploration of androgens after changing main androgens (delta 4 A, T, DHEA, DHEA S) into estrogens through the action of placental aromatase, as well as appreciation of aromatase activity of some tissues in the presence of androgenic substrates. This paper gives the conclusions after 5 years of practice with this method and summaries different works published by the biologists who developed the method and by the clinicians who used its results.
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PMID:[Enzymatic determination of urinary estrogens. A 5-year experience in a hospital milieu]. 383 76

FSH plays a central role in normal reproductive function, i.e. control of follicular maturation in the female and initiation and maintenance of spermatogenesis in the male. The effects of FSH are mediated by its interaction with a specific receptor that belongs to the superfamily of guanine nucleotide-binding protein-coupled receptors. Due to the microheterogeneity of gonadotropins, measurement of immunoreactivity does not necessarily reflect their bioactivity. Mutations in gonadotropin beta-subunits, which affect bioreactivity and/or immunoreactivity of gonadotropins, have been described as causes of infertility, thus highlighting the need for rapid and convenient methods to measure bioactivity. To establish a model system for recombinant in vitro bioassays for FSH that would obviate the use of live animals, we developed a strategy for efficient expression of the rat FSH receptor (FSHR) in L cells. A cell line, FSHR 7/12, was developed that bound [125I]FSH with high affinity (Kd 1.42 nM) and responded to human FSH with an increase in cAMP accumulation. Untreated human serum was found to have an unspecific inhibitory effect on cAMP formation. This effect could be thoroughly avoided by mild heating (10 min at 56 C) of serum samples before addition to cells without detectable loss of FSH immunoactivity or bioactivity. Studies on the hormone-sensitive adenylyl cyclase system of transformed FSHR 7/12 cells and of the parental Ltk- cells showed that the cellular response to FSH was highly specific. Using a parallel line assay design, FSHR 7/12 cells were used to validate a novel recombinant in vitro bioassay relying on intracellular cAMP accumulation as a readout system. Up to 10% of serum could be added to the incubation buffer without leading to nonparallelism to the standard curve. When 70 serum samples of male patients attending an infertility clinic were analyzed, the novel assay system displayed high sensitivity and a close correlation (r > 0.8; P < 0.01) to the established rat Sertoli cell aromatase bioassay and to a highly specific fluoroimmunoassay. When sera of 25 normal menstruating women were analyzed for FSH bioactivity at different stages of the menstrual cycle, a midcycle FSH peak followed by a decline in the late luteal phase could be discerned. The analysis of 26 serum samples of postmenopausal women revealed a close correlation between FSH values obtained by the novel in vitro bioassay and by a fluoroimmunoassay (r = 0.90; P < 0.01). Thus, the present in vitro bioassay represents a sensitive, rapid, and convenient model system to measure bioactive FSH in human serum.
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PMID:In vitro bioassay for human serum follicle-stimulating hormone (FSH) based on L cells transfected with recombinant rat FSH receptor: validation of a model system. 795 43


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