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PubMed1975

Metabolism of D- and L-norgestrel in humans.

Levels of DL-norgestrel, D-norgestrel, L-norgestrel and norethisterone were measured in blood by radioimmunoassay after oral administration of the progestin to 3 healthy male subjects and the half-lives calculated. Half-lives for D-norgestrel were much lower than those of L-norgestrel and similar to those of norethisterone. Measurement of norgestrel in blood can therefore be misleading unless the biologically active D-isomer is estimated. Since there was no difference in half-lives between norgestrel and norethisterone the greater potency of the former is probably due to it more strongly binding to target organ receptors.

Half-Life↗
PubMed1983

In vitro hydroxylation of the synthetic gestagen, norgestrel.

The in vitro metabolism of stereo-isomers (D, L and the racemic mixture DL) of norgestrel by a microsomal fraction from rabbit liver was investigated. The metabolism of the biologically active D-norgestrel was more rapid than that of L-norgestrel which is biologically inactive. This was mainly due to the more ready conversion of D-norgestrel to ring-A reduced metabolites. There was no difference between the two isomers in respect of the amount undergoing hydroxylation; about 40% of each isomer was converted to hydroxylated metabolites after 30 min incubation. However, there were differences between the isomers, D-norgestrel being converted mainly to the 16 beta-hydroxysteroid and L-norgestrel to the 16 alpha-hydroxysteroid. Similar amounts of both isomers were hydroxylated at C-6. The metabolism of the racemic mixture was intermediate between that of the D and L isomers.

Animals↗
PubMed1977

The detection and measurement of D-norgestrel in human milk using Sephadex LH 20 chromatography and radioimmunoassay.

An accurate sensitive method for the assay of D-norgestrel in human milk is described. The steroid is isolated from an ether extract of milk by Sephadex LH 20 chromatography in the system iso-octane-benzene-methanol (70:20:10 v/v). The radioimmunoassay utilises a specific antibody produced in rabbits against D-'norgestrel 3-(O-carboxymethyl) - oxime coupled to bovine serum albumin with D-norgestrel 3-(0-carboxymethyl) -oxime/ [125I]-iodohistamine conjugate as radioligand. Accuracy, sensitivity and blank value are satisfactory. Milk samples were obtained from three subjects treated with 30 microgram/day D-norgestrel, treatment commencing two weeks following parturition. Significant amounts of D-norgestrel were found, ranging between 92-135 pg/ml milk at the end of the first two-week treatment regimen. In two of three subjects, lower, but significant concentrations (53 pg and 35 pg/ml respectively) of steroid were found at the end of four weeks treatment. In the third subject, D-norgestrel could not be detected at this time. As a check on the specificity of the assay, three samples were submitted to additional chromatographic purification on alumina thin layer in the system benzene-cyclohexane-ethanol (70:27:3 v/v). Although this additional chromatographic step yielded somewhat lower values, agreement between the respective sets of results was good. The significance and implications of these findings are discussed.

Chromatography, Gel↗
PubMed2006

Effects of L-norgestrel on the endothelium-dependent relaxation response of rabbit clitoral cavernous smooth muscles.

OBJECTIVE: To determine the effect of a popular oral contraceptive, L-norgestrel (a synthetic progestogen), on relaxing response of clitoral cavernous smooth muscles. DESIGN: Prospective, randomized study. SETTING: Academic facility. ANIMAL(S): Thirty adult female New Zealand White rabbits. INTERVENTION(S): We conducted isometric tension studies with norepinephrine, endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators, and L-norgestrel. The effects of nonspecific nitric oxide synthase inhibitor (N(w)-nitro-L-arginine methyl ester) and the potassium channel blockers (1 and 10 mM tetraethylammonium as well as 10 microM glibenclamide) on the reactivities of clitoral cavernous strips were investigated. MAIN OUTCOME MEASURE(S): Causation and power of developed tension after treatment. RESULT(S): Acetylcholine, sodium nitroprusside, and L-norgestrel produced concentration-dependent relaxation of the norepinephrine-precontracted strips. Both endothelium removal and treatment with 10 microM N(w)-nitro-L-arginine methyl ester completely inhibited the relaxation response to acetylcholine and L-norgestrel, and supplementation with 10 mM L-arginine partially reversed the inhibition. Incubation with either tetraethylammonium (TEA) or glibenclamide reduced the L-norgestrel-induced relaxation in a dose-independent manner. CONCLUSION(S): The L-norgestrel-induced relaxation of the clitoral cavernous smooth muscle is endothelium and nitric oxide dependent and may be related to more than two types of potassium channels activation.

Acetylcholine↗
PubMed1996

Ethinyl oestradiol plus dl-norgestrel or levonorgestrel in the Yuzpe method for post-coital contraception: results of an observational study.

This observational study compares the efficacy and incidence of side-effects between dl-norgestrel (2 mg) and levonorgestrel (1 mg) associated with ethinyl oestradiol (200 micrograms) given in two doses 12 h apart for emergency post-coital contraception. A total of 117 consecutive women were given dl-norgestrel in combination with the oestrogen (dl-norgestrel group) while 423 consecutive subjects received the combination ethinyl oestradiol/levonorgestrel (levonorgestrel group). Overall, four (0.8%) pregnancies occurred in the 540 treated women, one (0.9%) in the dl-norgestrel group and three (0.7%) in the levonorgestrel group. In addition to this similar high contraceptive efficacy between both study groups, women in the levonorgestrel group had a significantly lower incidence of side-effects (23.5%) and better timing of the next menstruation after treatment (75% had bleeding on time) than those in the dl-norgestrel group (corresponding figures were 50.5 and 62.6% respectively). It is concluded that levonorgestrel should be used in preference to dl-norgestrel for post-coital contraception in the Yuzpe regimen.

Adolescent↗
PubMed1975

D-norgestrel slow-releasing T device as an intrauterine contraceptive.

A D-norgestrel slow-releasing T device was tried as an IUD in 100 fertile multiparous women for 6 months. The preliminary results were very encouraging. Not a single case of unintended pregnancy or removal due to excessive pain and bleeding was reported. The menstrual patterns and amounts of blood loss during menses did not reveal any marked variations. 3-H-D-norgestrel was used to study the in vitro release rate of D-norgestrel. The in vivo release rate was studied with the use of horseshoe-shaped silicone rubber capsules loaded with D-norgestrel as a temporary device. The uptake of intrauterine H-D-norgestrel in the circulation and genital tissues was estimated in two women.

Female↗
PubMed2005

Protective effect of nordihydroguaiaretic acid (NDGA) against norgestrel induced genotoxic damage.

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan and possesses antioxidant and number of properties potentially useful to man. The effect of NDGA was studied against norgestrel induced genotoxic damage, using sister chromatid exchanges (SCEs), chromosomal aberrations (CAs), mitotic index (MI) and replication index (RI) as parameters. Amounts of 5, 10 and 20 microM of norgestrel was tested for its genotoxic effect in the absence as well as presence of S9 mix, and was found to be genotoxic at 10 and 20 microM in the presence of S9 mix. Again, 10 microM of norgestrel was treated with 0.5 and 1 microM of NDGA, separately, in the presence of S9 mix. Similar treatment was given with 20 microM of norgestrel. Treatments given with NDGA result in the reduction of SCE, CA and increase of MI as well as RI, suggesting its protective action on human lymphocytes in vitro against the norgestrel induced genotoxic damage.

Antimutagenic Agents↗
PubMed2000

Simultaneous quantitative determination of norgestrel and progesterone in human serum by high-performance liquid chromatography-tandem mass spectrometry with atmospheric pressure chemical ionization.

A selective, reliable and rapid method for the simultaneous determination of progesterone and norgestrel concentrations in human serum after taking oral contraceptive tablet has been developed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) with atmospheric pressure chemical ionization (APCI) interface. The norethisterone was used as the internal standard. Selected transitions of m/z 313/245 for norgestrel, m/z 315/97 for progesterone and m/z 299/109 for norethisterone were monitored using multiple reaction monitoring (MRM) mode for quantitation. The assay was linear over the concentration range of 0.2-50 ng mL-1 for norgestrel and progesterone. The lower level of quantitation in human serum was obtained at 0.2 ng mL-1 for both norgestrel and progesterone using optimum tuning parameters. The intra-assay precision and inter-assay precision do not exceed 10 and 9%, respectively. The method has been applied to the determination of norgestrel and progesterone in serum of female volunteers.

Adult↗
PubMed1983

L-norgestrel and progesterone have different influences on plasma lipoproteins.

Twenty-six postmenopausal women who had been on cutaneous oestradiol treatment for 3-6 months were given either 120 micrograms of 1-norgestrel (n = 13) or 300 mg of progesterone (n = 13) sequentially for another 6 months. The concentrations of cholesterol, phospholipids and triglycerides were determined in plasma and in the HDL, HDL2, HDL3, LDL and VLDL fractions before and after one, three and six cycles of progestin treatment. Already after 11 days on 1-norgestrel, the mean HDL cholesterol and the mean HDL phospholipid concentrations were reduced by 15%. The reduction of the HDL-lipids was mainly confined to the HDL2 fraction which was decreased by 25-30%. L-norgestrel also reduced the mean TG concentration both in the VLDL and the combined LDL + HDL fractions. Progesterone gave only minor changes of the plasma lipids and lipoproteins. Reduced HDL, especially HDL2, concentration, as induced by 1-norgestrel, might increase the risk for ischaemic heart disease. Therefore, it seems that, as regards the effects on the lipoproteins, progesterone might be more suitable than the 19-nortestosterone derivative 1-norgestrel for postmenopausal sequential hormonal therapy.

Cholesterol↗
PubMed1972

Clinical and laboratory findings in a trial of norgestrel, a low-dose progestogen-only contraceptive.

Norgestrel, a progestogen-only oral contraceptive, was given continually at a dose of 75 mug/day to 144 women of proved fertility. It was an efficient contraceptive with a failure rate of 2.1% (assessed by the "life-table" method) within the first 12 cycles and 3.6% within the first 30 cycles (or 2.0 conceptions per 100 woman-years when assessed by the Pearl index). The overall conception rate for the entire trial period was 2.1% and 1.3 pregnancies per 100 woman-years respectively. Norgestrel caused a high proportion of irregular and generally short bleeding intervals, about one-fifth of the cycles lasting less than 17 days. This irregularity appeared to be due to individual variance in cycle length between women rather than that between their successive cycles. No confirmed instances of thromboembolism were observed. Norgestrel apparently exerts its contraceptive action by several mechanisms: reduction in the sperm penetrability of the cervical mucus and an impairment of luteal function appear important. The serum concentrations of cholesterol and globulin were significantly reduced in women taking norgestrel. Preliminary observations suggest that on discontinuing the medication fertility is promptly restored. Of the 144 women originally enrolled 57 (40%) withdrew for reasons connected with the method before completing 30 months on trial, over half of them because of the irregular menstrual pattern. Nonetheless, in view of its main clinical and laboratory characteristics and simple mode of administration, norgestrel appears to be a useful alternative to the combined type of pill for women unsuitable for, or unable to tolerate, oestrogen-containing preparations.

Blood Chemical Analysis↗
PubMed1980

Plasma levels of ethinyl oestradiol and norgestrel during hormone replacement therapy.

Plasma levels of levonorgestrel and ethinyl oestradiol were estimated in six women who took part in a double blind cross-over trial of hormone replacement therapy. Over a 12 mth period, each woman received each of the following oral drugs for 3 mth: ethinyl oestradiol 50 microgram, levonorgestrel 250 microgram, combination of ethinyl oestradiol 50 microgram and levonorgestrel 250 microgram (Nordiol), and placebo. Plasma samples were collected at 2, 8 and 26 h after morning medication each month. Plasma levels of norgestrel were increased when ethinyl oestradiol was added in the form of the combined preparation "Nordiol". The addition of ethinyl oestradiol to norgestrel therapy also resulted in significant differences between patients in the plasma norgestrel levels. There was approximately a three-fold difference between individuals in the plasma levels of ethinyl oestradiol achieved on the same fixed dose. No simple relationship was evident between plasma levels of norgestrel or ethinyl oestradiol and any of the clinical features measured.

Adult↗
PubMed2006

Tracking of enantioselective solubility of rac-norgestrel in the presence of cyclodextrin by a CD spectroscopic method.

Dissolution of hydrophobic rac-norgestrel in aqueous gamma-cyclodextrin (gamma-CyD) and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD) solutions was investigated, and enantioselective dissolution was observed. (-)-Norgestrel, the eutomer molecule, was dissolved to a greater extent using each of the CyDs, although the effect was more significant in the case of HP-gamma-CyD. A circular dichroism (CD) spectroscopic method based on measurement of the anisotropy factor was applied for the determination of the enantiomer ratio. The concentration and the enantiomer ratio of norgestrel were determined indirectly in octanol after extraction. Optical rotation dispersion (ORD) measurements could confirm that neither the free CyDs nor their inclusion complexes could get into the organic phase during transport to octanol. Only the norgestrel molecules were able to get into the organic phase, although the enantiomer ratio remained the same as was obtained in the aqueous CyD solution.

Circular Dichroism↗
PubMed1978

Sustained intrauterine release of d-norgestrel.

Clinical experience with seventy-two first insertions of a d-norgestrel-releasing IUD is reported. Plasma d-norgestrel concentrations were measured in twelve subjects. No pregnancies occurred in the 522 woman-months of use (averaging 7.3 months/subject) that have been accumulated. Removals were performed in six subjects for medical reasons and in seven subjects for personal reasons. Plasma concentrations of d-norgestrel were highest during the first two weeks of use. A decline in the plasma concentration of d-norgestrel occurred and was only 0.05 ng/ml between 30 and 90 days after insertion.

Adult↗
PubMed1979

Some estrogenic effects of two oral contraceptives consisting of norgestrel and two different doses of ethynylestradiol.

Some biological and biochemical effects (i.e. KPI, cervical mucus, SHBG and ceruloplasmin) as well as serum ethynylestradiol and serum norgestrel, following the use of two oral contraceptives containing the same amount of norgestrel (dl-norgestrel 0.5 mg) and either 30 microgram or 50 microgram of ethynylestradiol were compared. There was no difference in the clinical features in either group of patients. There was a statistically significant difference in the levels of unconjugated ethynylestradiol but not in the other biochemical parameters studied. It is concluded that the absence of any such difference might be attributable to the strong antiestrogenic effects of dl-norgestrel.

Adolescent↗
PubMed1976

Luteinizing hormone and progesterone in women under postcoital contraception with D-norgestrel.

Luteinizing hormone (LH) and progesterone (Pg) levels in blood were measured simultaneously by radioimmunoassay during 53 menstrual cycles in order to investigate the effect of 400 mug of D-norgestrel, administered postcoitally, on pituitary and ovarian function. Of 31 control cycles, 2 appeared to be anovulatory, since the LH peak and subsequent Pg elevation were absent. Twenty-nine cycles showed typical LH surges in the middle of the cycle, followed by a manifold Pg increase. Twelve women received 5 to 13 tables of D-norgestrel. A total absence or at least marked suppression of LH and Pg elevations was observed. In a third group, D-norgestrel was administered on scheduled days. Each woman ingested one to four tablets between the 6th and 18th days of the cycle. Two or more tablets disturbed LH and Pg ovulatory patterns. Of four women who received a tablet on day 10, one failed to show characteristic ovulatory patterns and three exhibited a delay in the time of the LH and Pg increase. These results demonstrate that D-norgestrel in a postcoital regimen alters pituitary and ovarian function, strongly suggesting an antiovulatory effect.

Contraceptives, Postcoital↗
PubMed2001

Evaluation of genotoxic potential of synthetic progestins-norethindrone and norgestrel in human lymphocytes in vitro.

The genotoxicity study of two widely used contraceptive synthetic progestins, i.e. norgestrel and norethindrone was carried out on human lymphocyte chromosomes using chromosomal aberrations (CA), sister chromatid exchanges (SCE) and cell growth kinetics as parameters. The study was carried out both in the presence as well as in the absence of metabolic activation (S(9) mix). The lymphocytes were exposed to three different concentrations of the drugs (20, 40 and 75 microg/ml for norethindrone and 10, 25 and 50 microg/ml for norgestrel) for three different durations (24, 48 and 72 h). The drug norethindrone was found to be non-genotoxic at any concentration and at any exposure duration either in the presence or in the absence of S(9) mix. But another drug norgestrel was found to affect the genetic material. It induces CA, SCE at significant level, and inhibits lymphocyte proliferation at 25 and 50 microg/ml of concentrations only. In the presence of S(9) mix the values obtained for CA, SCE and mitotic index (MI) were more significant. A time and dose relationship was also observed. It was concluded that norgestrel itself and possibly its metabolites are potent mutagens beyond a particular dose in human lymphocytes.

Cell Cycle↗
PubMed1993

Norgestrel and gestodene stimulate breast cancer cell growth through an oestrogen receptor mediated mechanism.

There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Oestrogens are known to stimulate the growth of human breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norprogestins stimulated proliferation at a concentration of 10(-8) M, while MPA could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be blocked by the antioestrogen ICI 164,384, but not by the antiprogestin RU486. Transfection studies with the reporter plasmids containing an oestrogen response element or progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellular action of norgestrel and gestodene. The 19-norprogestins stimulated the vitERE-CAT activity maximally at 10(-6) M, and this stimulation was inhibited by the addition of ICI 164,384. MPA did not stimulate vitERE-CAT activity. A single base pair alteration in the palindromic sequence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the progestin activity required specific response element base sequencing. PRE15-CAT activity was stimulated by norgestrel, gestodene and MPA at concentrations well below growth stimulatory activity. This stimulation could be blocked by RU486. These studies suggest that the 19-norprogestins norgestrel and gestodene stimulate MCF-7 breast cancer cell growth by activating the oestrogen receptor.

Base Sequence↗
PubMedDate not supplied

Excretion and stereoselective biotransformations of dl-, d- and l-norgestrel in women.

Excretion data and urinary metabolite patterns of di-, d-, and l-norgestrel were obtained from women who received a single, oral 1.5-mg dose of 14C-labeled racemic norgestrel (Ng) or one of its enantiomers. The average percentage of administered radioactivity +/- SD recovered in the urine after 7 days was 58.1 +/- 7.9% for dl-Ng, 44.8 +/- 8.9% for d-Ng, and 63.6 +/- 15.1% for l-Ng; in feces it was 23.4 +/- 7.7% (dl-Ng), 31.6 +/- 8.2% (d-Ng), and 24.8 +/- 10.7% (l-Ng). Different metabolite patterns were observed for each enantiomer in urine, and the pattern for the racemate appeared to be an approximate composite of the metabolite patterns of the two enantiomers. These differences in the metabolite pattern result from stereoselective transformations; notably 16 beta-hydroxylation of l-Ng and ring A reduction of d-Ng. Other stereoselective pathways noted were: 16 alpha- and 1 beta-hydroxylation as well as D-homoannulation of l-Ng and sulfate conjugation of l-16 beta-hydroxynorgestrel; 2 alpha-hydroxylation of d-Ng, formation of a labile neutral, polar compound which contained the norgestrel moiety in the d-form, and formation of a glucuronide of d-16 beta-hydroxynorgestre. The formation of phenolic derivatives occurred to a very minor degree from transformations of the biologically inactive l-enantiomer. With d-norgestrel, this formation occurred to an even lesser extent, if at all.

Adult↗