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PubMed1989

Blood-spot 17-hydroxyprogesterone in nonclassical 21-hydroxylase deficiency.

The value of blood-spot 17-hydroxyprogesterone (17-OHP) measurements in selective screening for non-classical 21-hydroxylase deficiency (NC 21-OHD) among female patients with postnatal virilization was studied. Early morning basal blood-spot and serum samples, and post-ACTH serum samples for 17-OHP measurement were collected from twenty-seven patients with precocious pubarche, hirsutism and/or menstrual abnormalities (age: 3 to 17 years). Using a two-step extraction method for blood-spot 17-OHP measurements of all the nine patients with NC 21-OHD showed higher values than the eighteen patients without 21-OHD. Blood-spot 17-OHP values of patients with NC 21-OHD showed a diurnal rhythm with pathological high levels between 0500 and 0900 h, and normal or slightly elevated levels between 1700 and 2100 h. In conclusion, early morning blood-spot 17-OHP measurement is a useful method to detect NC 21-OHD in the peripubertal period.

Adolescent↗

PubMed1975

Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor.

We conducted a double-blind study to determine the efficacy of 17alpha-hydroxyprogesterone caproate in preventing premature delivery in 43 high-risk patients. Premature delivery did not occur in 18 patients receiving the progestational agent, whereas 41 per cent of the 22 receiving the palcebo had premature delivery (P less than 0.01). The mean duration of pregnancy and the mean birth weight in the former group (38.6 weeks +/- 1.6 S.D., and 2836 g +/- 412 S.D.) were both significantly greater (P less than 0.025) than that in the latter (35.2 weeks +/- 6.7 S.D.; 2361 g +/- 1085 S.D.). The perinatal mortality rate in the group given the progestational agent (O per cent) was significantly less than that observed in the placebo group (27 per cent) (P less than 0.05). Although there were no complications attributable to the progestational drug, the study population was too small for assessment of immediate or long term safety. However, the results indicate a possible obstetric use for this drug.

Adult↗

PubMed1985

Total synthesis of (+/-)-11 alpha-hydroxyprogesterone by cyclization of a polyunsaturated epoxide.

The total synthesis of a typical 11-hydroxylated steroid, (+/-)-11 alpha-hydroxyprogesterone, was achieved by picric acid-catalyzed tricyclization of a polyunsaturated epoxide appropriately substituted with ketal, hydroxyl, and acetylenic units. This epoxide was prepared by a multistage sequence featuring two successive alkylations of intermediary, monocyclic sulfones. The first sulfone intermediate was obtained by means of a short sequence starting from levulinic acid and diethyl succinate and involving a selective cyclization reaction.

Cyclization↗

PubMed2005

Determination of 17alpha-hydroxyprogesterone in serum by liquid chromatography-tandem mass spectrometry and immunoassay.

17Alpha-hydroxyprogesterone (17OHP) is the most important serum marker for congenital adrenal hyperplasia (CAH). 17OHP is usually measured by immunoassay but its detection by mass spectrometry (MS) is a potentially superior method. An LC-MS (liquid chromatography-mass spectrometry) method was developed which utilizes 0.5 ml serum spiked with 6-alpha-methylprednisolone (6-MP) or deuterated 17OHP (d8-IS) as the internal standard. The samples were extracted with ether/ethylacetate, and the extract was evaporated to dryness and analysed by LC-MS/MS operating in the positive mode after separation on a reversed-phase C18 column. The calibration curves for analysis of serum 17OHP exhibited consistent linearity and reproducibility in the range of 5-250 nmol/l. Interassay CVs were 8.5 and 9.2% at mean concentrations of 7.9 and 23 nmol/l, respectively. The detection limit was 1 nmol/l (signal-to-noise ratio=3). The mean recovery of 17OHP added to serum ranged from 76 to 89% and that of internal standards from 75 to 82%. The regression equation for the LC-MS/MS (x) and in-house radioimmunoassay (RIA) (y) methods was: y=0.87x+0.26 (r=0.97; n=100) and for a commercial RIA it was: y=1.32x+0.02 (r=0.97; n=26).

17-alpha-Hydroxyprogesterone↗

PubMed2002

Non-classical 21-hydroxylase deficiency in children: association of adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk of compound heterozygosity with severe mutations.

AIM: To investigate the association between levels of 17-hydroxyprogesterone (17-OHP) and the risk of being compound heterozygous for severe mutations in children with non-classical 21-hydroxylase deficiency (NC21OHD). METHODS: In 86 Spanish NC21OHD children (75 families) an analysis of the 21-hydroxylase (21-OH) gene was performed by CYP21B-specific polymerase chain reaction amplification, allele-specific oligonucleotide hybridization and Southern blotting. Familial analysis established how the alleles segregated, and allowed the selection of 21-OH-genotyped normal and carrier children, which proved useful in determining a more precise definition of the cut-off for diagnosis. Receiver operating characteristics (ROC) curve analyses were performed to determine the potential value of 17-OHP in predicting compound heterozygosity for severe mutations. RESULTS: Thirty-four of the 86 children (39%) were found to carry one severe 21-OH mutation (7.3% deletions or conversions, 2.7% 655G, 2.7% Q318X, 1.3% 1172N, 1.3% R356W, and 3.3% double microconversions or small conversions involving single exons). The predominant mutation was V281L (56.7%). P453S and P30L were less frequent (3.3 and 2%). No patient showed two severe mutations. The degree of enzymic deficiency, as measured by basal or adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels in fully genotyped patients, but not clinical severity (age and number of symptoms at diagnosis), was found to be significantly greater in children with the severe/mild genotype. ROC curve analyses revealed a strong association between ACTH-17-OHP and genotype (area under the curve 0.908, SE 0.057). CONCLUSION: ACTH-stimulated 17-OHP may predict the risk of severe mutations in compound heterozygosity in children (maximum predictive value 93% sensitivity and 83% specificity for a cut-off at 151 nmol l(-1)), although a certain overlap in individual values is observed and performance of molecular analysis should never be obviated in the genetic counselling of these patients.

17-alpha-Hydroxyprogesterone↗

PubMed2006

Production and characterization of monoclonal antibodies against 17alpha-hydroxyprogesterone.

Hybridomas secreting monoclonal antibodies (MAbs) against 17alpha-hydroxyprogesterone (17OHP) have been generated. These MAbs are highly specific and have an affinity of 7-12 x 10(7) M(1). The hybridomas were obtained by fusion of spleen cells from immunized mice with mouse myeloma P3X63 Ag8.653 cells. The antigen used for immunization was 17OHP conjugated to bovine serum albumin (17OHP:BSA). Fused cells were plated and cloned in 96-well microtiter plates. Wells containing hybridomas were screened simultaneously for specific gamma globulin (IgG) and anti-17OHP activity using an enzyme-linked immunosorbent assay (ELISA)-based method, which is faster than the conventional radioimmunoassay (RIA) screening procedure. Limiting dilution methods were used to obtain single hybridoma clones producing MAb. The stable hybridomas secreting anti-17OHP MAbs were expanded into bioreactors or ascites fluid for large-scale production of the required antibodies. These MAbs will be used in the formulation of a 17OHP assay kit to screen for congenital adrenal hyperplasia (CAH) in local newborn human population.

17-alpha-Hydroxyprogesterone↗

PubMed1997

17-Hydroxyprogesterone responses to gonadotrophin-releasing hormone agonist buserelin and adrenocorticotrophin in polycystic ovary syndrome: investigation of adrenal and ovarian cytochrome P450c17alpha dysregulation.

Abnormal regulation of cytochrome P450c17alpha causes the exaggerated secretion of ovarian androgens in polycystic ovary syndrome (PCOS). This enzyme is active in both the ovaries and adrenal glands. We examined whether there is an abnormal regulation of cytochrome P450c17alpha in the adrenal gland by investigating the relationship of 17-hydroxyprogesterone (17-OH progesterone) hyperresponsiveness to the gonadotrophin releasing hormone (GnRH) agonist, buserelin, testing with 17-OH progesterone response to adrenocorticotrophic hormone (ACTH) in PCOS. In all, 68 women with PCOS and 24 normal women were included in the study. Ultrasound, clinical and hormonal parameters were used to define PCOS. 17-OH progesterone response to ACTH was measured in all the women. In 52 of the 68 women with PCOS, 17-OH progesterone response to buserelin was measured. The mean basal 17-OH progesterone concentrations were similar in both PCOS and control groups. PCOS women had significantly higher net increment in 17-OH progesterone after ACTH administration (P<0.02). No significant correlations were found between the peak 17-OH progesterone values, the net increments in 17-OH progesterone and the area under the 17-OH progesterone-response curves after ACTH stimulation and buserelin test. Although 17-OH progesterone response to ACTH was significantly higher in the patients with PCOS than in the control subjects, the lack of relationship between 17-OH progesterone response to GnRH agonist buserelin and 17-OH progesterone response to ACTH stimulation suggests that the dysregulation of the cytochrome P450c17alpha enzyme may not play a role in adrenal androgen excess seen in PCOS.

17-alpha-Hydroxyprogesterone↗

PubMed1982

Silastic implants of progesterone produce high circulating levels of both progesterone and 20 alpha-hydroxyprogesterone in ovariectomized, adrenalectomized rats.

Previous studies indicated that circulating 20 alpha-hydroxyprogesterone (20 alpha-OH-P) in cyclic female rats derived from enzymatic conversion of progesterone in corpus luteum tissue (Hashimoto and Wiest, 1969). A possibility of extraovarian conversion of progesterone to 20 alpha-OH-P also was revealed by our recent finding that placement of Silastic implants of progesterone produced not only high plasma progesterone but also 20 alpha-OH-P in ovariectomized (OVX), previously pseudo-pregnant, rats (Gilman et al., 1981). This study was performed to measure the amounts of serum 20 alpha-OH-P and progesterone in intact or adrenalectomized (ADX), cyclic female rats and in OVX, ADX or OVX-ADX animals with or without progesterone implants. Twenty-four-hour patterns of serum progestins revealed that OVX rats exhibited low progesterone secretion (3-6 ng/ml) and undetectable levels of 20 alpha-OH-P in the absence of ovaries. In intact, cyclic females, circulating concentrations of 20 alpha-OH-P were 4- to 6-fold greater than those or progesterone. ADX resulted in a partial reduction of progesterone but not 20 alpha-OH-P in the circulation. Placement of 4 cm Silastic implants of progesterone produced high serum concentrations of both progesterone (29 +/- 4 ng/ml, mean +/- SEM) and 20 alpha-OH-P (27 +/- 1 ng/ml) in OVX and OVX-ADX rats. These findings demonstrate that placement of progesterone implants into female rats produces high circulating concentrations of both progesterone and 20 alpha-OH-P, and indicate that an extraovarian and extra-adrenal system(s) for progestin conversion is functioning under persistently high circulating progesterone conditions. By this system, large amounts of circulating progesterone are transformed into a less potent progestational compound, 20 alpha-OH-P.

Adrenalectomy↗

PubMed2005

17 hydroxyprogesterone for the prevention of preterm delivery.

The recent publication of 2 large randomized trials of 17 alpha hydroxyprogesterone caproate (17P) and progesterone suppositories, respectively, for the prevention of premature labor have renewed interest in the use of progesterone to prevent preterm birth. The results of these trials have reinforced the positive results of earlier smaller trials of 17P to prevent preterm delivery. A large body of evidence attests to the lack of teratogenic effects of 17P in pregnancy. Although progesterone is known to have many actions beneficial to the maintenance of pregnancy, the exact mode of action of 17P therapy in preventing preterm labor and delivery is not known. Current evidence supports the use of 17P treatment, begun early in the second trimester of gestation and continued weekly until 36 weeks, for women with a history of a previous spontaneous preterm delivery. At present no evidence exists for the use of 17P to prevent preterm delivery in women with multiple gestation, a short uterine cervix, or other high-risk conditions. The use of 17P or other progestins should not be encouraged for these indications outside of randomized trials. At present no evidence exists for the efficacy of any oral progesterone compound in preventing preterm labor. Four trials reporting the use of a progestational drug in patients with symptoms of preterm labor found no efficacy in prolonging pregnancy, and the use of 17P or other progestational drugs as tocolytic therapy should not be encouraged.

17-alpha-Hydroxyprogesterone↗

PubMed1981

Blood-spot 17 alpha-hydroxyprogesterone radioimmunoassay in the follow-up of congenital adrenal hyperplasia.

The value of plasma 17 alpha-hydroxyprogesterone (17 alpha-OHP) concentration in monitoring the treatment of congenital adrenal hyperplasia (CAH) was studied by using a capillary blood micromethod. The blood-spot 17-OHP radioimmunoassay method involves serial sampling throughout the day and sending the samples into the centre by mail. Follow-up of seven children treated for CAH due to 21-hydroxylase deficiency showed that a single measurement of plasma 17-OHP concentration cannot be relied upon to determine adequacy of control, since circadian variation and timing of the sample in relation to the last dose of glucocorticoid may influence the plasma level of 17 alpha-OHP. Our data confirm the value of sequential 17 alpha-OHP assays throughout the day in the follow-up of CAH. With the blood-spot method the 17 alpha-OHP determinations can be used on a wide scale for monitoring therapy.

Adolescent↗

PubMed1987

Comparison of the effects of etomidate and its fluoro analogue, R 8110, on plasma cortisol, 11 beta-deoxycortisol, 17 alpha-hydroxyprogesterone and testosterone concentrations in dogs.

R 8110, an imidazole derivative, was shown to be clinically superior to etomidate for induction and maintenance of anaesthesia in dogs. The present study compared the effects of intravenous (i.v.) R 8110, etomidate and Ringer solution on cortisol biosynthesis by the adrenal gland in seven male labradors. A tetracosactide challenge was carried out 30 min after the i.v. injection of 3 mg/kg of both drugs and after i.v. Ringer solution (1 ml/kg). Etomidate and R 8110 both suppressed the cortisol response to tetracosactide almost completely and increased the plasma 11 beta-deoxycortisol levels more than 20 fold. Maximal 11 beta-deoxycortisol values were reached 120 min after R 8110, and not less than 300 min after etomidate. Plasma 17 alpha-hydroxyprogesterone and testosterone concentrations did not differ between placebo and R 8110 treatment, but they decreased after etomidate. These results indicate that the effects of R 8110 on steroid biosynthesis in dogs are less pronounced than those of etomidate and are largely limited to a temporary inhibition of the 11 beta-hydroxylase in the adrenal gland.

17-Hydroxycorticosteroids↗

PubMed1978

Secretion patterns of plasma-progesterone, 17-hydroxyprogesterone and 20 alpha hydroxypregn-4-en-3-one in early normal pregnancy.

Plasma levels of progesterone, 17-hydroxyprogesterone and 20 alpha hydroxypregn-4-en-3-one were established from 4 to 16 weeks gestation by sampling 15 normal patients twice weekly. Apart from a peak at week 5, the mean levels of progesterone remained constant at about 24 ng/ml until week 10 and then rose progressively to 40 ng/ml at week 16.20 alpha hydroxypregn-4-en-3-one remained within the 7 to 9 ng/ml range apart from a peak at week 5. A significant decrease in mean levels of 17-hydroxy-progesterone was noted from week 5 to a nadir of 3 ng/ml at week 11. It would appear that the main hormone production of progesterones in pregnancy has been taken over by the placental unit by the 10th week.

20-alpha-Dihydroprogesterone↗

PubMed1978

Secretion patterns of plasma-progesterone, 17-hydroxyprogesterone, and 20alpha hydroxypregn-4-en-3-one in early abnormal pregnancy.

Plasma progesterone, 17-hydroxyprogesterone, 20alpha hydroxypregn-4-en-3-one levels were determined twice weekly up to 16 weeks gestation, where possible, in a twin pregnancy, in two patients who aborted spontaneously and in three patients who were treated with 'progesterone supplements' because of abnormal vaginal cytology. There was no correlation between vaginal smears and the plasms hormone levels and there was no evidence to suggest that progesterone supplements influenced clinical outcome. Compared with normal mean values the only difference was a significantly rise in progesterone and 20alpha hydroxypregn-4-en-3-one levels in the twin pregnancy after the 12th week and a precipitate fall in all hormone levels just prior to abortion. Plasma hormone levels could not be used to predict outcome.

20-alpha-Dihydroprogesterone↗

PubMed1979

Ouabain receptor binding of hydroxyprogesterone derivatives.

1 A specific and sensitive radioreceptor assay ahs been devised which is based on high affinity, saturable binding of 9 nM [3H]-ouabain to the total particulate fraction isolated from dog heart. Ouabain and other cardiac glycosides, including the aglycones, were about equipotent in their ability to displace [3H]-ouabain from its receptor, the IC50s ranging from 10 to 30 nM. 2 The only other substances found to compete significantly in the assay were derivatives of hydroxyprogesterone having a 17 alpha-acetate substituent: chlormadinone acetate, megestrol acetate, cyproterone acetate and medroxyprogesterone acetate, with IC50s of 2, 7.4, 9 and 21 microM, respectively. Prednisolone-3,20-bisguanyl-hydrazone, reported to have inotropic activity, gave an IC50 of 6.4 microM. Cyproterone-17 alpha-OH was less active (IC50 90 microM) than cyproterone-17 alpha-acetate. 3 A large number of peptide and protein hormones, steroid hormones and their metabolites, amines, and drugs were inactive.

Animals↗

PubMed1979

17-Hydroxyprogesterone in normal children and congenital adrenal hyperplasia. Measurement in serum by radioimmunoassay after thin-layer chromatography.

Serum 17alpha-hydroxyprogesterone (17 OH-P) was measured by a specific radioimmunoassay technique combined with thin-layer chromatography. Normal values for children are less than 1.1 microgram/1 (less than 3.3 nmol/l)--corresponding to values found in the literature. In congenital adrenal hyperplasia (CAH) values up to several hundred microgram/l are found. The values rise after ACTH stimulation and are suppressed by decadrone or cortisone treatment. The rise in 17 ketosteroids and pregnanetriol in untreated CAH is relatively smaller (15--25 fold). This clinical sensitivity of 17 OH-P is thus valuable for the diagnosis of CAH (21 hydroxylase deficiency). Furthermore it is easier to take a blood sample than to collect urine for 24 hours. The usefulness in therapeutic monitoring is being studied.

17-Ketosteroids↗

PubMed1981

"Dot-17 alpha-hydroxyprogesterone" radioimmunoassay for identification of congenital adrenal hyperplasia in young infants.

Using a simplified radioimmunoassay method for the determination of 17-hydroxyprogesterone (17-OHP) concentration in blood dried on filter paper seven untreated cases of congenital adrenal hyperplasia were identified among newborns and infants at risk for congenital adrenal hyperplasia (CAH) having ambiguous genitalia and/or failure to thrive with electrolyte disturbances. In three additional cases the diagnosis of congenital adrenal hyperplasia was confirmed by high 'dot-17-OHP' values even after glucocorticoid therapy had been started. Capillary blood samples taken in a local hospital on a filter paper routinely used for the screening of phenylketonuria can be sent by mail into a central laboratory for performing the analysis. Assays of 'dot-17-OHP' are clearly of diagnostic value in the C21-hydroxylase form of CAH and permit a rapid diagnosis of this condition in the newborn period.

Adrenal Hyperplasia, Congenital↗

PubMed2006

Alterations in hepatic metabolism of adult male rats following exposure to hydroxyprogesterone during embryonic development.

AIM: To investigate the effect of in utero exposure to hydroxyprogesterone (HP) on liver metabolism in adult male albino rats. METHODS: Pregnant Wistar strain albino rats were exposed to supra-normal levels (10 mg/kg and 25 mg/kg) of HP on days 1, 7 and 14 of pregnancy. The male pups were maintained under controlled conditions and the rats were killed 90 days after birth. The liver tissue was immediately excised, weighed and used for biochemical assays. RESULTS: The activity levels of succinate dehydrogenase (SDH), glutamate dehydrogenase (GDH), glucose-6-phosphate dehydrogenase (G-6-PDH), malate dehydrogenase (MDH) and aminotransaminases were significantly increased in the livers of rats exposed to HP during embryonic development. The lactate dehydrogenase (LDH) activity level was significantly decreased in the liver of experimental rats. Furthermore, there was a significant elevation of activity levels of antioxidant enzymes (glutathione S-transferase [GST] and catalase [CAT]) with an increased lipid peroxidation in the hepatic tissue of experimental rats compared with the control group. CONCLUSION: The results of the present study suggest that there is an increase in the oxidative metabolism, antioxidative mechanism and levels of lipid peroxidation in rats exposed to HP during embryonic development. The increased aminotransaminase activities in these rats reveal tissue damage and disruption of mitochondrial integrity.

17-alpha-Hydroxyprogesterone↗

PubMed2006

The glucuronidation of Delta4-3-Keto C19- and C21-hydroxysteroids by human liver microsomal and recombinant UDP-glucuronosyltransferases (UGTs): 6alpha- and 21-hydroxyprogesterone are selective substrates for UGT2B7.

The stereo- and regioselective glucuronidation of 10 Delta(4)-3-keto monohydroxylated androgens and pregnanes was investigated to identify UDP-glucuronosyltransferase (UGT) enzyme-selective substrates. Kinetic studies were performed using human liver microsomes (HLMs) and a panel of 12 recombinant human UGTs as the enzyme sources. Five of the steroids, which were hydroxylated in the 6beta-, 7alpha-, 11beta- or 17alpha-positions, were not glucuronidated by HLMs. Of the remaining compounds, comparative kinetic and inhibition studies indicated that 6alpha- and 21-hydroxyprogesterone (OHP) were glucuronidated selectively by human liver microsomal UGT2B7. 6alpha-OHP glucuronidation by HLMs and UGT2B7 followed Michaelis-Menten kinetics, whereas 21-OHP glucuronidation by these enzyme sources exhibited positive cooperativity. UGT2B7 was also identified as the enzyme responsible for the high-affinity component of human liver microsomal 11alpha-OHP glucuronidation. In contrast, UGT2B15 and UGT2B17 were the major forms involved in human liver microsomal testosterone 17beta-glucuronidation and the high-affinity component of 16alpha-OHP glucuronidation. Activity of UGT1A subfamily enzymes toward the hepatically glucuronidated substrates was generally low, although UGT1A4 and UGT1A9 contribute to the low-affinity components of microsomal 16alpha- and 11alpha-OHP glucuronidation, respectively. Interestingly, UGT1A10, which is expressed only in the gastrointestinal tract, exhibited activity toward most of the glucuronidated substrates. The results indicate that 6alpha- and 21-OHP may be used as selective "probes" for human liver microsomal UGT2B7 activity and, taken together, provide insights into the regio- and stereoselectivity of hydroxysteroid glucuronidation by human UGTs.

Cell Line↗