Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sex hormone binding globulin (SHBG) is a specific steroid-binding plasma glycoprotein regulated by several factors. Sex steroids are currently considered to be the main physiological regulators of this protein. SHBG levels, in fact, increase during estrogen treatment and decrease after androgen administration. It is well known, however, that in many physiological and pathological conditions SHBG concentrations cannot be explained only on the basis of steroidal control mechanisms. The regulation of SHBG levels is in fact more complex and other factors can also affect its plasma values. Between the steroidal factors our attention was focused on the role of androgens, of glandular and peripheral origin, in their capacity to lower SHBG plasma levels. We studied hyperandrogenic conditions in prepubertal (65 subjects with precocious adrenarche and 16 girls with prepubertal hypertrichosis, aged between 4 and 8 years) and in adult age (51 hirsute patients aged between 14-35 years and 51 acneic patients aged between 15-40 years). The effects of dexamethasone and ACTH administration on SHBG plasma levels were also evaluated. The results obtained showed that in adult hyperandrogenic patients SHBG levels, significantly lower than in controls, were not always inversely correlated with androgen levels, which, on the contrary, were higher than in controls. In patients with precocious adrenarche we found an inverse correlation only between SHBG, which was significantly lower than normal, and body mass index or bone age but not with androgens, suggesting that in this condition other factors may be more relevant than steroids in SHBG regulation. Between the non-steroidal factors our attention focused on insulin. We studied 40 non-obese hyperandrogenic patients with or without ultrasonographic evidence of polycystic ovaries, aged 18-39 years, and 35 obese patients, aged 19-37 years, with or without hyperandrogenism or evidence of PCO. Low levels of SHBG were found not only in hyperandrogenic obese patients but also in obese patients with normal androgens. It is possible to conclude that (1) several factors (calorie intake, energy balance and growth factors), other than steroids, may be involved in the regulation of SHBG levels in plasma; and (2) each regulating factor may act to a different extent depending on the various periods of the life cycle.
J Steroid Biochem Mol Biol 1992 Oct
PMID:Steroidal and non-steroidal factors in plasma sex hormone binding globulin regulation. 139 Feb 92

In a longitudinal study of 82 children we found a gradual rise in median plasma concentrations of 11 beta-hydroxyandrostenedione (11 beta-OH-A4) from 2.5 to 6.4 nmol/l during childhood which was similar in both sexes. This could reflect changes in adrenal function during the adrenarche and sexual maturation. Plasma concentrations of 11 beta-OH-A4 in adults follow the patterns of cortisol secretion. In patients with diseases of the adrenal cortex, the plasma concentrations of 11 beta-OH-A4 were consistent with the pathology of each condition. In women with polycystic ovaries (PCO) undergoing gonadotrophic stimulation for in vitro fertilization and embryo transfer, 11 beta-OH-A4 (median = 3.8 nmol/l), testosterone and androstenedione, were raised when compared to women with normal ovaries (11 beta-OH-A4 median = 2.6 nmol/l). Follicular fluid has concentrations of 11 beta-OH-A4 six to twelve times greater than plasma levels and in women with PCO, 11 beta-OH-A4 concentrations were lower than in women with normal ovaries, which is consistent with an inhibition of ovarian 11 beta-hydroxylase. Granulosa cells in vitro demonstrated the production of 11 beta-OH-A4 by side chain cleavage of cortisol. These data support an adrenal source for 11 beta-OH-A4 but the raised plasma concentrations in women with polycystic ovary syndrome (PCOS) may reflect the excess androgen output from the ovary. 11 beta-OH-A4 may therefore be an additional marker for ovarian dysfunction.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Studies to confirm the source of 11 beta-hydroxyandrostenedione. 153 6

We investigated whether plasma androstanediol glucuronide (ADG) levels reflect the increased androgenicity in women with idiopathic hirsutism (n = 24) or hirsutism associated with polycystic ovary syndrome (n = 10). We also evaluated whether ADG levels parallel the clinical evolution of the hirsutism during a combined treatment, with cyproteroneacetate (2 mg) and ethinylestradiol (35 micrograms), of women with moderate idiopathic hirsutism. Finally, we investigated if there is evidence for increased conversion of precursors to ADG in hirsutism, by comparing the ADG levels, measured by RIA, to ADG levels obtained by applying the conversion rates of precursors obtained in non-hirsute women. ADG levels were increased in less than half of the patients with mild hirsutism. The clinical cure of hirsutism, which was obtained by the treatment in majority of patients, was accompanied by a significant decrease of plasma ADG levels, but a similar decrease was also observed in the 5 patients who did not respond to treatment. The data show that, although there is evidence for increased conversion of precursors to plasma ADG in mildly hirsute women, the latter is not a reliable parameter of androgenicity. Our data suggest, moreover, that treatment with cyproterone acetate and ethinylestradiol decreases 5 alpha-reductase activity, as indicated by the more important decrease in ADG levels than in the precursors.
J Steroid Biochem Mol Biol 1991 Jul
PMID:Is plasma 5 alpha-androstane 3 alpha, 17 beta-diol glucuronide a biochemical marker of hirsutism in women? 182 56

In an analysis of 263 women with polycystic ovary syndrome (PCOS), 91 (35%) of whom were obese (body mass index greater than 25 kg/m2), it was found that obese women with PCOS were more likely to be anovulatory and had a higher prevalence of hirsutism than the non-obese subgroup. Although serum concentrations of gonadotrophins, androstenedione and total testosterone were similar in obese and lean women with PCO, sex hormone binding globulin (SHBG) levels were significantly lower, and free testosterone correspondingly higher, in obese women. Serum concentrations of SHBG were inversely correlated with those of both fasting and glucose-stimulated insulin. A short-term, very-low-calorie diet resulted in a 2-fold increase in SHBG which was mirrored by a fall in serum insulin. Similar biochemical changes were also observed during a long-term (6-7 months) 1000 kcal diet and were associated with an improvement of menstrual function and fertility. This encourages the view that calorie restriction has an important part to play in the management of obese women with PCOS.
J Steroid Biochem Mol Biol 1991 Nov
PMID:The role of nutrition and insulin in the regulation of sex hormone binding globulin. 195 73

The mechanism of the ovarian dysfunction in polycystic ovary syndrome, the most common cause of anovulatory infertility, remains obscure. Clinical data suggest that follicle stimulating hormone (FSH) action may be inhibited at the ovarian level by paracrine factors derived, presumably, from interstitial cells. The greater responsiveness to FSH of granulosa cells isolated from polycystic ovaries (PCO) compared with that seen in cells derived from normal ovaries, provides some support for this hypothesis and we present data which suggests that epidermal growth factor, or more likely transforming growth factor alpha, could be a candidate for this inhibitor. It should be emphasized, however, that the cardinal biochemical feature of the PCO is hypersecretion of androgens by interstitial cells. Stromal tissue from the PCO will secrete significant quantities of androstenedione in response to LH, whereas there is a negligible response in stroma from normal ovaries. It remains to be determined whether androgens have a direct inhibitory effect on FSH-induced oestradiol production in the human follicle, or whether they might exert an indirect effect by activating inhibitory polypeptide growth factors.
J Steroid Biochem Mol Biol 1991
PMID:Polycystic ovary syndrome: interaction of follicle stimulating hormone and polypeptide growth factors in oestradiol production by human granulosa cells. 195 41

Antiandrogens, preventing androgen action at target tissue level, are used in the treatment of various androgen-dependent diseases. Pharmacologically these substances have either a steroidal structure, like cyproterone acetate (CPA) and spironolactone (SPL), or a non-steroidal structure, like flutamide (FLU). In women with hyperandrogenism (PCO syndrome, idiopathic hirsutism, acne), clinical benefit may be obtained with CPA, which also displays a progestational activity and an antigonadotropic effect. CPA (25-50 mg/day) is used in combination with ethinyl-estradiol (EE) (20-30 micrograms/day) in reversed sequential regimen. SPL, less effective than CPA may be employed in moderate hirsutism and acne at dosages of 100-200 mg/day. During SPL treatment menstrual irregularities are frequent: in this case an association with oral contraceptives is indicated. SPL + bromocriptine (2.5-5 mg/day) has been experienced with success in PCO syndrome. The pure antiandrogen FLU, inducing progressive increase in LH and testosterone secretion, may be used only in combination with oral contraceptives. In men antiandrogens have been tested in BPH and prostatic carcinoma. In BPH the decrease in nuclear receptors and DHT nuclear content during CPA or FLU may represent the rational base of the medical treatment. An improvement in urinary obstructive manifestation has been observed with CPA alone or associated with tamoxifen (100 mg + 100 mg day). In advanced prostatic carcinoma antiandrogens represent a good alternative to estrogen therapy with less side effects and in combination with surgical or medical castration (LH-RH analogues) achieve a complete androgen blockade. An increase in the percentage of remissions and survival has been reported.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Antiandrogens: clinical applications. 214 59

Although sex steroids have long been known to influence serum concentrations of SHBG, it is now recognized that nutritional factors may be more important in the regulation of SHBG in women. Thus, SHBG concentrations are negatively correlated with body mass index (BMI) and, more particularly, to indices of central adiposity. Polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility, is associated with truncal obesity, hyperandrogenism and hyperinsulinaemia. There is evidence that insulin may be the humoral mediator of the weight-dependent changes in SHBG. Serum SHBG concentrations are inversely correlated with both fasting and glucose-stimulated insulin levels, and insulin has been shown to have a direct inhibitory effect on SHBG synthesis and secretion by hepatocytes in culture. However, the interrelationship of BMI, insulin and SHBG appears to be different in women with PCOS from that in normal subjects. The clinical importance of the weight-related suppression of SHBG is illustrated by the finding of a greater prevalence of hirsutism in obese women PCOS compared with their lean counterparts. Obese subjects with PCOS have similar total testosterone concentrations to lean PCO women but have lower SHBG and reciprocally higher free testosterone levels. Calorie restriction results in reduction of serum insulin followed by an increase in SHBG and a fall in free testosterone but an isocaloric, low-fat diet has no significant effect on SHBG concentrations. Weight reduction in obese, hyperandrogenaemic women with PCO is an important approach to the management of both anovulation and hirsutism.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Sex hormone-binding globulin and female reproductive function. 762 5

Zeneca ZM244085, 9-(3 cyanophenyl)hexahydro-1,8 acridinedione, is a novel dihydropyridine (DHP) which relaxes KCl precontracted urinary bladder smooth muscle in vitro. The effect of ZM244085 on low and high KCl induced contractions, 86Rb efflux and [3H]-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. Since ZM244085 is a dihydropyridine its effect on DHP binding sites on Ca2+ channels was also investigated. ZM244085 was found to be more potent in relaxing detrusor strips precontracted with 15 mM KCl than strips precontracted with 80 mM KCl (Li et al., 1995). This functional profile of ZM244085 is similar to that exhibited by typical K-channel openers (PCO). In addition, inhibition of ZM244085 induced relaxation of detrusor strips by glibenclamide suggests that ZM244085 opens ATP sensitive K-channel (KATP) in urinary bladder (Li et al., 1995). Since the glibenclamide sensitive smooth muscle relaxation activity of ZM244085 could still be an indirect effect of this compound on KATP channels we carried out 86Rb efflux studies and [3H]-P1075 binding studies to further confirm these findings. The 86Rb efflux assay is a direct method for monitoring the movement of K+ ions across the cell membranes. Displacement of [3H]-P1075 binding to bladder membranes supports a direct action of the compound on the KATP channel. The present study demonstrates that ZM244085 in a concentration dependent manner increases the rate of 86Rb efflux from guinea pig bladder strips. This effect was inhibited by glibenclamide (30 microM), a known KATP channel blocker. In addition, interaction of ZM244085 with KATP channels was also confirmed in human bladder smooth muscle cells using a 42K efflux assay. Furthermore, we were able to demonstrate that ZM244085, structurally distinct PCO, inhibited the binding of 3H-P1075 to urinary bladder strips in a manner similar to other KATP openers such as cromakalim and pinacidil. Inhibition of 3H-P1075 binding by ZM244085 and other PCO's correlates well with increases in 86Rb efflux and bladder muscle relaxation studies. Finally, ZM244085 did not exhibit any significant affect on VSCC as evidenced by very weak inhibition of [3H]-PN200,110 binding to bladder membranes by ZM244085. It is concluded that Zeneca ZM244085 is a PCO which activates KATP channels in urinary bladder.
Res Commun Mol Pathol Pharmacol 1995 May
PMID:K-channel opening activity of dihydropyridine ZM244085: effect on 86Rb efflux and 3H-P1075 binding in urinary bladder smooth muscle. 767 Aug 46

Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.
Hum Mol Genet 1994 Oct
PMID:Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. 784 15

The aim of this work is to evaluate the gonadotropin and growth factor effects in vitro on steroidal response in human granulosa luteal cells from polycystic ovaries compared with normal granulosa luteal cells in humans. The granulosa cells from polycystic (polycystic ovarian granulosa cells, POGC) and normo-ovulating women (normal cells, NC) were collected in the preovulatory phase after oocyte retrieval during the GIFT program. The cells were cultured serum-free for 24, 48 and 96 h. Estradiol and progesterone production was determined with or without HCG (1-200 ng/ml), FSH (10-300 ng/ml), insulin (1-50 micrograms/ml) and IGF I (1-50 ng/ml) addition. All treatments significantly induced a 2-3 fold estradiol increase at the 48-h and 96-h time points in POGC. The progesterone production was unaffected by HCG, FSH, insulin and IGF I addition, respectively, in POGC, whereas the NC were responsive at the 48-h and 96-h time points. FSH did not stimulate progesterone production in granulosa cells either from polycystic or normovulating subjects. Our findings indicate that POGC are hypersensitive to all substances in terms of estradiol production, whereas they show a reduced capacity of progesterone production with some treatments.
Mol Cell Endocrinol 1994 Dec
PMID:Effect of gonadotropins, insulin and IGF I on granulosa luteal cells from polycystic ovaries. 789 19


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