Norgestrel

Crystals from methanol

Crystals from diethyl ether-hexane

Danger

H315 (11.1%): Causes skin irritation [Warning Skin corrosion/irritation]；H319 (11.1%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H351 (92.6%): Suspected of causing cancer [Warning Carcinogenicity]；H360 (88.9%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H362 (88.9%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]；H400 (88.9%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]；H410 (88.9%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

P203, P260, P263, P264, P264+P265, P270, P273, P280, P302+P352, P305+P351+P338, P318, P321, P332+P317, P337+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 27 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including norgestrel, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /In combination with Ethinylestradiol/

Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Store at controlled room temperature 15 °C to 25 °C (59 °F to 77 °F).

Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Wash spill site. Place spillage and all contaminated cleanup materials in a thick plastic hazardous waste disposal bag or leakproof container and label it CAUTION: HAZARDOUS CHEMICAL WASTE.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

This material is assumed to be combustible. As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

Engineering controls such as exhaust ventilation are recommended.

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. The completeness of the cleaning procedures should be considered before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at the end of shift, but should remain at employee's place of work for cleaning.

For more Preventive Measures (Complete) data for NORGESTREL (6 total), please visit the HSDB record page.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible. Eye Protection: Safety goggles or glasses. Protective clothing: Protect exposed skin.

The metabolism of estrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (eg phenobarbital, phenytoin, carbamazepine), and anti-infectives (eg rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's Wort (Hypericum Perforatum) may induce the metabolism of estrogens and progestagens.

Phenytoin and rifampin increase the serum concentrations of sex hormone-binding globulin (SHBG); this significantly decreases the serum concentration of free drug for some progestins, which is a special concern in patients using progestins for contraception. /Progestins/

Drug interaction data are not available for rifabutin, but because its structure is similar to that of rifampin, similar precautions with its use with progestins may be warranted. ... /Progestins/

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8,100(SRC), determined from a structure estimation method(2), indicates that norgestrel is expected to be immobile in soil(SRC). Volatilization of norgestrel from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Norgestrel is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8100(SRC), determined from a structure estimation method(2), indicates that norgestrel is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.7X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 91(SRC), from an estimated log Kow of 3.48(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), norgestrel, which has an estimated vapor pressure of 1.0X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase norgestrel may be removed from the air by wet or dry deposition(SRC). Norgestrel contains chromophores that absorb at wavelengths >290 nm(4), and therefore may be susceptible to direct photolysis by sunlight(SRC).

Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of norgestrel can be estimated to be 8,100(SRC). According to a classification scheme(2), this estimated Koc value suggests that norgestrel is expected to be immobile in soil.

/HUMAN EXPOSURE STUDIES/ The growth hormone, insulin, and blood glucose values were measured during a glucose tolerance test in 12 women before and after 3 months' use of a sequential contraceptive (11 pills containing .05 mg D-norgestrel and .05 mg ethinyl estradiol and 10 pills containing .05 mg D-norgestrel and .05 mg ethinyl estradiol). Neither fasting blood glucose nor glucose tolerance are altered during administration of the contraceptive steroids. Conversely, the reactive insulin level is significantly increased in comparison to the basal value, thus showing the signs of hyperinsulinemia. Both the gestagens and the estrogens appear to contribute to this disturbance of insulin secretion. Presumably the hyperinsulinemia is an expression of decreased sensitivity of the peripheral tissue to insulin. The growth hormone, a so-called insulin antagonist, is not responsible for the insulin resistance observed. The values measured after administration of the contraceptive do not significantly differ from the basal values.

/SIGNS AND SYMPTOMS/ Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea, and withdrawal bleeding may occur in females.

/CASE REPORTS/ ... Presented is the case of a 45-year-old US woman with right lower quadrant pain and a 5-year history of use of a combined oral contraceptive (OC) containing 0.35 ug ethinyl estradiol and 0.35 ug norgestrel. At presentation, the uterus was enlarged to a size corresponding to 12-14 gestational weeks, with a mass at the right fundal margin. Pelvic ultrasonography revealed a large dominant leiomyoma 7.2 x 5.8 x 5.5 cm and several smaller tumors. OC use was discontinued and, 4 months later, the uterus was a size of 8-10 gestational weeks and a single serosal leiomyoma 5.9 x 4.6 x 4.4 cm remained. The leiomyoma volume had decreased by 47% after OC discontinuation, to 63 cu cm. Pelvic sonography 12 months after OC discontinuation revealed no further changes in myoma volume. In OC users with clinically significant uterine leiomyomas, discontinuation of combined OCs should be considered as a low-risk intervention with the potential to decrease uterine volume.

/CASE REPORTS/ /Investigators/ report a 41-year-old Caucasian woman with polycystic liver and kidney disease, and a 9-year history of severe cyclical urticaria related to her menses. The urticaria was not adequately controlled by antihistamines or Prempak-C (conjugated oestrogens and norgestrel). Intradermal testing with progesterone was strongly positive at 30 min and 18 hr. Buserelin, administered intranasally at doses of up to 800 ug daily, controlled the urticaria within 4 weeks, and she was completely symptom-free thereafter. She had therapy-induced amenorrhea and occasional hot flushes. Unfortunately, her liver cysts progressively enlarged, and a right hepatectomy was performed in June 1992, but she died after complications 3 weeks later. Prior to this she had been free of urticaria for 6 months after starting buserelin. Buserelin, a gonadotrophin-releasing hormone analogue, may be useful in the management of progesterone-induced urticaria, in patients in whom conjugated estrogens are contraindicated or unhelpful.

For more Human Toxicity Excerpts (Complete) data for NORGESTREL (33 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

norgestrel

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 92 was calculated in fish for norgestrel(SRC), using an estimated log Kow of 3.48(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for norgestrel is estimated as 7.7X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that norgestrel is expected to be essentially nonvolatile from water and moist soil surfaces(2). Norgestrel is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-9 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Castrated (C3H x RIII)F1 mice ... of both sexes were fed dL-norgestrel or d-norgestrel in the diet at levels of 1 or 0.5 mg/kg, respectively. Mammary carcinomas were observed in 22/31 dL-norgestrel treated, 27/34 d-norgestrel treated and 17/29 control female mice. In the corresponding males, the incidences were 9/32, 10/32 and 10/61. The increases in incidence /for females/ were slightly raised, but the latencies of mammary tumors were unchanged.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Rats were given 0.5-30 ug norgestrel orally from day 1-7 of gestation or 2 ug on days 6-8, or in a single dose /of 2 ug/ on day 6, 7 or 8. Administration of 2 ug continuously for 7 days terminated 100% of pregnancies; a single dose was effective only when given on day 6, terminating 57% of pregnancies; 2 ug given on days 6-8 terminated 50% of pregnancies.

/ALTERNATIVE and IN VITRO TESTS/ The effect of synthetic progestins found in oral contraceptives has potential implications for developing embryos in women who receive oral contraceptives during early pregnancy. /Investigators/ assessed the effect of the progestin norgestrel on the developing pre-embryo. B3C6F1 mice were given 5 IU PMSG followed by 5 IU hCG 48 hr later. Studies were performed on pre-embryos recovered and pooled at both 24 hr (Group A) and 48 hr (Group B) post hCG. At each time period, they were randomly assigned to control or norgestrel (4.0 ng/mL) treatment. In a third study, pre-embryos collected 24 hr post hCG were cultured in the absence or presence of 8.0, 80.0, or 800 ng/mL norgestrel. Cultures were performed in Ham's F-10 media with 10% fetal calf serum at 37 degrees C in an atmosphere of 5% CO2, 5% O2 and 90% N2 with 15-30 embryos per 1 mL of culture fluid. At 24 hr, 48 hr and 72 hr post recovery, cultures were viewed, the appearance of embryos noted, and number of blastomeres recorded. Compared to control groups, analysis demonstrated no significant difference in the rate of development of control and norgestrel pre-embryos in any group at any time period (24 hr, 48 hr, or 72 hr post recovery). /The authors/ conclude that norgestrel at the dose tested has no acute adverse morphological effects on development of mouse pre-embryos. This observation has potential clinical implications with regard to inadvertent use of norgestrel-containing oral contraceptives during early days of pregnancy, as well as consideration of the mechanism of action of norgestrel-containing "morning after" pills.

/ALTERNATIVE and IN VITRO TESTS/ Norgestrel at concentrations of 10(-8)-10(-6) mol/L stimulated the growth of the estrogen receptor-containing and estrogen-sensitive mammary cancer cell lines MCF-7 and T47D:A18; this activity was inhibited by the anti-estrogen ICI182,780 and ICI164,384 (at concentration of 10(-6) mol/L), but not by RU486 (at concentration of 10(-7) mol/L).

Oral contraceptives have been reported to produce harmful ocular effects in myopic women. In women who developed myopia at or near puberty and in whom myopia became stable in adulthood, the drugs have reportedly increased the refractive error 2- to 3-fold, usually after 6 months of use. In women who are myopic and have considerable astigmatism, oral contraceptives may produce marked changes in the astigmatic error, possibly leading to frank keratoconus. In addition, oral contraceptives may produce a rapid advancement of the ocular disorder in patients with a family history of marked myopic astigmatism or keratoconus. Contact lens wearers receiving estrogen-progestin contraceptives may have more difficulties with their contact lenses than do nonusers who wear contact lenses. Contact lens wearers who develop visual disturbances or changes in lens tolerance during estrogen-progestin contraceptive use should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. /Estrogen-Progestin Combination/

Mental depression may occur in women receiving oral contraceptives. In a few cases, mental depression has been severe and has led to suicidal behavior. Mental depression appears to occur most frequently in patients with a history of depression, including premenstrual depression; however, relief of premenstrual tension occurs in some women. Patients with a history of mental depression should be observed carefully and the estrogen-progestin contraceptive discontinued if severe depression recurs during use. /Estrogen-Progestin Combination/

Norgestrel is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Norgestrel contains chromophores that absorb at wavelengths >290 nm(1), and therefore may be susceptible to direct photolysis by sunlight(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including norgestrel, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /In combination with Ethinylestradiol/

Norgestrel (and more specifically the active stereoisomer levonorgestrel) binds to the progesterone and estrogen receptors within the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins like levonorgestrel will slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH (luteinizing hormone) surge. Loss of the LH surge inhibits ovulation and thereby prevents pregnancy.

Combination oral contraceptives act by suppression of gonadotrophins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cer-vical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which may reduce the likelihood of implantation).

Progestins enter target cells by passive diffusion and bind to cytosolic (soluble) receptors that are loosely bound in the nucleus. The steroid receptor complex initiates transcription, resulting in an increase in protein synthesis. /Progestins/

Progestins are capable of affecting serum concentrations of other hormones, particularly estrogen. Estrogenic effects are modified by the progestins, either by reducing the availability or stability of the hormone receptor complex or by turning off specific hormone-responsive genes by direct interaction with the progestin receptor in the nucleus. In addition, estrogen priming is necessary to increase progestin effects by upregulating the number of progestin receptors and/or increasing progesterone production, causing a negative feedback mechanism that inhibits estrogen receptors. /Progestins/

There is great concern over the long-term influence of oral contraceptives on the development of breast cancer in women. Estrogens are known to stimulate the growth of human breast cancer cells, and /it/ has previously reported that the 19-norprogestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. /Investigators/ 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 estrogen 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 estrogen receptor.

(14)C-Norgestrel was administered to seven human subjects and 43% of dose was excreted in the urine within 5 days ... Enzymic hydrolysis released only 32% of the urinary radioactivity and a further 25% was excreted as sulphate conjugates. The metabolites excreted in the urine were much less polar than those following the administration of the related compounds, norethisterone or lynestrenol. The 3alphaOH,5beta and 3betaOH,5beta isomers of the tetrahydronorgestrel (13beta-ethyl-17alpha-ethynyl-5 beta-gonane-3alpha,17beta-diol) were isolated from urine and identified by mass spectrometry and thin-layer and gas-liquid chromatography. Plasma radioactivity decreased more rapidly than after the administration of norethisterone and lynestrenol. About 2% of the administered dose was converted to acidic compounds. There was no apparent difference in the rate of excretion of radioactivity or in the metabolites after either oral or intravenous administration of norgestrel.

The comparative metabolism of dl-, d-, and l-norgestrel was investigated in African Green Monkeys (Cercopithecus aethiops). Total (14)C excretion in urine after a single oral dose of (14)C-dl-norgestrel (1 mg/kg) was significantly higher (51.4 +/- 5.0%) than that observed after administration of the d-enantiomer (37.5 +/- 5.4%) but not the l-enantiomer (44.2 +/- 8.9%). In all cases, the major part of the urinary radioactivity was present in a free fraction (48-62%), while an additional 13-27% was released by beta-glucuronidase preparations. No sulfate conjugates were detected. At least one major (16beta-hydroxylation) and one minor (16alpha-hydroxylation) metabolic pathway were stereoselective, i.e., they are operative with the I-but not the d-enantiomer. Three metabolites, 16beta-hydroxynorgestrel, 16alpha-hydroxynorgestrel, and 16-hydroxytetrahydronorgestrel (believed to be 16beta) were only detected in urine samples obtained from (14)C-dland -l-norgestrel-dosed animals. Following (14)C-d-norgestrel administration, 3alpha, 5beta-tetrahydronorgestrel was found to be the major urinary metabolite. These observations are compared with those reported earlier on the urinary metabolites of dl-norgestrel in women.

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 l-norgestrel was more rapid than that of d-norgestrel (sic.) which is biologically inactive. This was mainly due to the more ready conversion of l-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, l-norgestrel being converted mainly to the 16beta-hydroxysteroid and d-norgestrel to the 16alpha-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.

The rates of metabolism of synthetic gestagens derived from 19-nortestosterone by rabbit liver tissue in vitro were compared. Over a period of 1 hr norethisterone was metabolized as rapidly as 19-nortestosterone whereas d-norgestrel and lynestrenol were metabolized at a slightly lower rate. Less than 5% of l-norgestrel was metabolized. In all cases the reaction product was the tetrahydrosteroid. Lynestrenol was metabolised through norethisterone. Skeletal muscle, lung and small intestine also metabolized norethisterone and d-norgestrel but at a slower rate than liver tissue. Small amounts of norethisterone were metabolized by adipose tissue but heart and spleen were inactive. Lynestrenol and l-norgestrel were not metabolized by any of the extra-hepatic tissues studied.

In vitro studies were conducted on the metabolism of 3 steroids used in OCs (oral contraceptives) by small pieces of human jejunal mucosa. This was done because the gastrointestinal mucosa of humans is known to metabolize a number of drugs. Almost 40% of the ethinyl estradiol, 9.8% of the levonorgestrel, and 7% of the mestranol were metabolized after incubation. All these metabolic responses were significantly different from those in the control groups. Results of the study show that the metabolism of the ethinyl estradiol was related to the weight of the tissue used. These results are consistent with the known marked 1st pass effect of ethinyl estradiol. Norgestrel, known to have little or no 1st pass effect, did not show a high rate of gut metabolism. Under the experimental conditions employed, no Phase 1 metabolism of either ethinyl estradiol or levonorgestrel was apparent.

Norgestrel is absorbed from the gastrointestinal tract, metabolised by the liver and excreted in the urine and faeces as glucuronide and sulphate conjugates.

(14)C-Norgestrel was administered to seven human subjects and 43% of dose was excreted in the urine within 5 days; the biological half-life of the radioactivity was 24 hr. Enzymic hydrolysis released only 32% of the urinary radioactivity and a further 25% was excreted as sulphate conjugates. The metabolites excreted in the urine were much less polar than those following the administration of the related compounds, norethisterone or lynestrenol. The 3alphaOH,5beta and 3betaOH,5beta isomers of the tetrahydronorgestrel (13beta-ethyl-17alpha-ethynyl-5 beta-gonane-3alpha,17beta-diol) were isolated from urine and identified by mass spectrometry and thin-layer and gas-liquid chromatography. Plasma radioactivity decreased more rapidly than after the administration of norethisterone and lynestrenol. About 2% of the administered dose was converted to acidic compounds. There was no apparent difference in the rate of excretion of radioactivity or in the metabolites after either oral or intravenous administration of norgestrel.

The binding of different synthetic steroids, used in hormonal contraception, to Sex Hormone Binding Globulin (SHBG) was studied by measuring their ability to displace tritiated testosterone from SHBG in a competitive protein binding system. Only 19-nortestosterone derivates had any significant ability to displace testosterone from SHBG, d-norgestrel (d-Ng) being the strongest displacer. Increasing the SHBG levels in women with previous constant plasma d-Ng levels increased these levels two- to sixfold. It is concluded that SHBG is the main carrier protein for d-Ng. The strong testosterone displacing activity of d-Ng might also explain androgenic side effects observed with d-Ng containig oral contraceptives.

MEDICATION

Use (kg; approx.) in Germany (2009): >50；Consumption (g per capita; approx.) in Germany (2009): 0.000611；Calculated removal (%): 24.5

In a representative chemical synthesis, 6-methoxy-alpha-tetralone is reacted with vinylmagnesium bromide, and the resulting 1,2,3,4-tetrahydro-6-methoxy-1-vinyl-1-naphthol is condensed with 2-ethyl-1,3-cyclopentanedione to form initially a tricyclic intermediate (secosteroid) containing all of the gonane skeleton carbon atoms. Cyclization of the secosteroid via dehydration yields a 13-ethylgona-1,3,5(10)-8,14-pentaene structure which is then successively reduced and ethynylated.

Prepn: H. Smith, Belg. pat. 623,844 (1963), C.A. 61, 4427c (1964); G.A. Hughes, H. Smith, U.S. pat. 3,959,322 (1976 to Herchel Smith)

Mixture of levonorgestrel with ethinyl estradiol. Levlen, Logynon, Microgynon, Nordette, Ovran, Ovranette, Tetre-gynon, Tri-Levlen, Trinordiol, Triphasil. Clinical trial in acne treatment.

Mixture with ethinyl estradiol. Lo/Ovral, Ovral, Stediril. Clinical efficiacy as oral contraceptive.

Norgestrel is available commercially as a single-ingredient tablet and as a component of combination tablets with ethinylestradiol, estradiol valerate or as combined injectable solution with ethinylestradiol.

Oral: Tablets: Norgestrel and Ethinyl Estradiol 0.3 mg/0.03 mg, Low-ogestrel (Watson Pharma).

Oral: Tablets: 2 mg estradiol valerate (white tablets taken day 1-11), 500 ug norgestrel + 2 mg estradiol valerate (pale brown tablets taken day 12-21), Cyclo-Progynova (Meda Pharmaceuticals).