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PubMed1992

Introduction to steroids in the menopause.

Menopausal symptoms and signs associated with the reduction of ovarian function include an increased incidence of cardiovascular disease and loss of bone mass as well as less serious but more uncomfortable symptoms such as vasomotor flushes and atrophy of the vaginal wall. Although unopposed estrogen effectively reverses these and other menopausal symptoms, it is well established that without the addition of progestin there is an unacceptably high risk of developing hyperplasia or cancer of the endometrium. Depending on the type and dose of progestin added, however, this addition may reverse estrogen's beneficial cardiovascular effects and produce unwanted side effects. Lower doses and newer progestins, such as norgestimate, gestodene, and desogestrel, have demonstrated a decreased potential to reverse the positive cardiovascular effects of estrogen while still eradicating persisting or de novo endometrial hyperplasia.

Endometrial Hyperplasia↗
PubMed1990

Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids.

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. Further studies on the metabolism of these progestogens are required before we can understand their mechanism of action.

Animals↗
PubMed2004

Enhancing oral contraceptive success: the potential of new formulations.

Reductions in oral contraceptive (OC) estrogen dose and the development of new progestins have resulted in formulations that maintain acceptable cycle control while improving safety. However, the potential safety benefits of low-estrogen doses may be offset by less acceptable cycle control. These observations have led to the development of 2 triphasic OC formulations containing norgestimate and desogestrel in combination with 25 microg ethinyl estradiol (EE). Both of these 25-microg EE triphasic OCs balance fewer estrogen-related side effects with good cycle control comparable to OCs containing higher estrogen doses. However, questions remain about the risk of venous thromboembolism associated with OCs containing desogestrel. A new monophasic 30-microg EE OC contains drospirenone, a spironolactone analogue with which there is limited experience. Although initial data with this OC are intriguing, product labeling highlights safety issues related to its antimineralocorticoid effects and the potential for hyperkalemia. Further experience with this formulation will determine its role in contraceptive practice.

Chemistry, Pharmaceutical↗
PubMed2005

Effect of oral versus transdermal steroidal contraceptives on androgenic markers.

OBJECTIVE: The purpose of this study was to compare biochemical androgen profiles in women treated with the contraceptive patch versus an oral contraceptive (OC). STUDY DESIGN: Twenty-four healthy women were randomly assigned to receive 3 cycles of either the contraceptive patch (ethinyl estradiol [EE] 20 microg/d and norelgestromin 150 microg/d) or OC (EE 35 mug and norgestimate 250 microg). Blood samples were taken at baseline and end of treatment. Serum levels of sex hormone-binding globulin (SHBG), total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), dihydrotestosterone (DHT), and 3alpha-androstanediol glucuronide (3alpha-diol G) were quantified by immunoassay methods; free T was calculated. The paired t and Student t tests were used for statistical analysis. RESULTS: Nineteen women completed the study (patch, n = 10; OC, n = 9). Despite a 1.6-fold relative increase in SHBG levels with the patch versus OC (449% vs 274%, P = .03), free T decreased equally in both groups (patch 60%, P < .0001; OC 59%, P < .0001). DHEAS decreased by 26% in the patch group (P < .01) and 32% in the OC group (P < .001). 3alpha-diol G was reduced by 52% in the patch group (P < .0001) and 51% in the OC group (P < .0001). In addition, the OC was associated with significant decreases in A and DHT. CONCLUSION: The contraceptive patch had an effect comparable to the OC on several key androgenic markers. Given these biochemical findings, the contraceptive patch has significant potential as a therapeutic agent for disorders of androgen excess.

Administration, Cutaneous↗
PubMed2004

In vitro and ex vivo evidence for modulation of P-glycoprotein activity by progestins.

The well known gender-related differences in drug action may partly be explained by changes in activity and expression of drug metabolising enzymes, but also by modulation of active drug transport systems (e.g. P-glycoprotein, Pgp) by sexual steroids, which is yet not well investigated. Because many women are using hormones (e.g. as oral contraceptives) we investigated the influence of different synthetic progestins on Pgp activity. Pgp inhibition of progesterone, medroxyprogesterone, chlormadinone, cyproterone, levonorgestrel, norethisterone, desogestrel, and norgestimate was measured in vitro in two Pgp over-expressing cell lines (L-MDR1, P388/dx cells) and the corresponding parental cell lines by means of calcein assay, and ex vivo in human peripheral blood mononuclear cells (PBMCs) by rhodamine123 efflux. For most progestins tested, concentrations needed to double baseline fluorescence (f2) in L-MDR1 cells were similar to that of the potent Pgp inhibitor quinidine, whereas levonorgestrel and norethisterone did not reach f2. The results in P388/dx cells essentially confirmed our findings in L-MDR1 cells. Additionally, Pgp inhibitory activity of all progestins tested was also shown ex vivo in PBMCs. The potent Pgp inhibition by several synthetic progestins in vitro and ex vivo suggests that such an interaction might be clinically relevant despite generally low plasma concentrations of progestins. The results may be of particular importance for Pgp substrates, such as protease inhibitors and chemotherapeutic agents, for which intracellular concentrations are critical.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study.

OBJECTIVE: The effects of long-term triphasic oral contraceptive administration on bone mineral density (BMD) were investigated in premenopausal women with hypothalamic amenorrhea (HA) and osteopenia. METHODS: After completing three 28-day cycles in the double-blind phase of a placebo-controlled trial, women (mean age, 26.7 years) who received norgestimate 180-250 microg/ethinyl estradiol 35 microg (NGM/EE, n = 15) or placebo (n = 12) in the double-blind phase were to receive open-label NGM/EE for 10 additional cycles. RESULTS: For subjects completing > or =10 NGM/EE treatment cycles, mean posteroanterior total lumbar spine BMD (L1-L4) increased from 0.881+/-0.0624 g/cm2 at baseline (last visit prior to NGM/EE) to 0.894+/-0.0654 g/cm2 at final visit (p = .043); no significant changes in hip BMD occurred. Decreases in N-telopeptide, osteocalcin, procollagen type I propeptide and bone-specific alkaline phosphatase levels indicated effects on bone metabolism. CONCLUSIONS: Long-term administration of triphasic NGM/EE to osteopenic women with HA may increase total lumbar spine BMD.

Absorptiometry, Photon↗
PubMed2005

Treating acne with oral contraceptives: use of lower doses.

Oral contraceptives (OCs) have been shown to effectively treat acne. Clinical trials of various doses of ethinyl estradiol (EE) combined with progestins such as levonorgestrel, desogestrel, norgestimate, gestodene, cyproterone acetate and drospirenone in monophasic, triphasic and combiphasic formulations used to treat acne in women are reviewed here. Open-label and comparative studies beginning in the 1980s were the first to demonstrate objective and subjective reductions in the incidence of acne, severity of existing acne and seborrhea. Placebo-controlled trials have corroborated these findings with a trend toward effective acne treatment with declining doses of EE. Significant reductions in total, inflammatory and noninflammatory lesions compared with placebo have been demonstrated with an OC containing the low dose of 20 microg of EE. Collectively, these findings support the use of low-dose OCs for the treatment of acne.

Acne Vulgaris↗
PubMed2006

Effects of transdermal and oral contraceptives on estrogen-sensitive hepatic proteins.

OBJECTIVE: The purpose of this study was to evaluate the effects of the contraceptive patch and an oral contraceptive (OC) on serum concentrations of estrogen-sensitive hepatic proteins, ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: Twenty-four women were randomized to receive three cycles of a contraceptive patch that delivers EE 20 microg/day and norelgestromin 150 microg/day or an OC that contains EE 35 microg and norgestimate 250 microg. Blood samples were taken at baseline and at the end of Cycle 3. Serum levels of sex-hormone-binding globulin (SHBG), thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG) and C-reactive protein (CRP) were quantified by immunoassay methods. EE and LNG levels in patch users were measured by radioimmunoassay (RIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The paired t test and Student's t test were used for statistical analysis. RESULTS: Nineteen women completed the study (patch, n=10; OC, n=9). Treatment with both the patch and OC resulted in significant increases from baseline in SHBG, TBG and CBG. The increase in CRP was significant in the patch group and approached significance in the OC group. The increases in SHBG and TBG observed with the patch were significantly greater than those associated with the OC. By way of RIA and LC-MS/MS assay methods, the patch was associated with mean EE levels of 114 and 111 pg/mL, respectively. CONCLUSIONS: The serum concentrations of estrogen-sensitive hepatic proteins and EE associated with the patch suggest that this new contraceptive system may have relatively large net estrogen effects.

Administration, Cutaneous↗
PubMed2006

Androgenicity of the progestin in oral contraceptives does not affect maximal leg strength.

PURPOSE: This study was conducted to examine androgenicity of the progestin in oral contraceptive pills and its effect on maximal leg strength in females. METHODS: Twelve participants who were using a monophasic pill containing 30 microg ethinylestradiol plus either 150 microg levonorgestrel (LEV) or 250 microg norgestimate (NOR) for at least the last 6 months were recruited (mean+/-SEM; LEV: age, 19.8+/-0.3 years; stature, 1.67+/-0.17 m; mass, 65.9+/-1.9 kg; NOR: age, 20.6+/-0.2 years; stature, 1.65+/-0.17 m; mass, 64.6+/-2.4 kg). Three maximal isokinetic extension and flexion tests were performed on three occasions (Days 3-6, 11-14 and 18-21 of the pill cycle) to assess peak extension and peak flexion torque (in Newton meters). RESULTS: No significant (p>.05) differences were found in the LEV and NOR groups in peak extension torque (F=0.719; p=.416) or peak flexion torque (F=0.291, p=.601) throughout the pill cycle and between groups. CONCLUSION: In this small study, the androgenicity of the progestin in the contraceptive pill had no significant association with maximal strength in these female athletes.

Adult↗
PubMed2006

[Pregnancies occurring during oral contraception: lessons from the GRECO study].

OBJECTIVES: The GRECO study has collected data on pregnancies, regardless of their outcome, that occurred in women taking an oral contraceptive. PATIENTS AND METHODS: The analysis concerned 551 women prospectively recruited in services of gynaecology or obstetrics, termination of pregnancy centres, family planning centres or consultations of gynaecology in France throughout 2002 and who were 12 weeks pregnant or less. RESULTS: Contraception used during the cycle of conception was an estroprogestative combination in 88% of cases, a microprogestative in 8.7%, a macroprogestative in 0.9% or another type of pill in 2.4%. Progestatives were levonorgestrel 59.0%, gestoden 17.2%, desogestrel 4.7%, norethisterone acetate 2.9%, norgestimate 1.8%, cyproterone acetate 2.0%, norgestrel 1.6%. When asked about the potential cause of the oral contraceptive failure, 76.9% of women reported events such as missed pills which were the most frequent cause of failure (60.8% of failures and 80.1% of events, 2.7+/-2.7 missed pills), followed by vomiting and diarrhoea. 81.5% of women chose to terminate their pregnancy. DISCUSSION AND CONCLUSION: The GRECO study, despite its limitations (retrospective collection of missed pills data, declaratory data) showed that missed pills, even once, were the most common reason for oral contraceptive failure. The most frequent decision was the termination of pregnancy.

Abortion, Induced↗
PubMed2006

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study.

PURPOSE: To evaluate the effect of an oral contraceptive (OC) on bone mineral density (BMD) in adolescent females with anorexia nervosa (AN) or eating disorder not otherwise specified (EDNOS). METHODS: Females 11-17 years of age with AN or EDNOS entered the study. Subjects were randomized equally to treatment with a triphasic OC containing norgestimate (NGM) 180-250 microg and ethinyl estradiol (EE) 35 microg or placebo for 13 28-day cycles. Dual energy x-ray absorptiometry scans (DXA) of the lumbosacral spine (LS) and hip were obtained at baseline and after 6 and 13 cycles. RESULTS: Demographic characteristics of the 112 subjects (NGM/EE 53; Placebo 59) who received study drug and had at least one on-treatment DXA were similar between groups for age (mean: 15 years in each group) and body mass index (mean: NGM/EE 17.9 kg/m2; Placebo 17.6 kg/m2). At the end of Cycle 6, there was a significant increase in the mean LS BMD in the NGM/EE group compared with placebo (.020 g/cm2 vs. .008 g/cm2; p = .021); however, at the end of Cycle 13 the mean increase in LS BMD in the NGM/EE group compared with placebo was no longer significant (.026 g/cm2 vs. .019 g/cm2, p = .244). There was no significant difference in change in hip BMD between groups. The incidence of adverse events was similar between groups. CONCLUSIONS: In a group of adolescent females with AN or EDNOS, treatment with a triphasic OC for 13 cycles did not have a statistically significant effect on LS or hip BMD.

Adolescent↗
PubMed2003

An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells.

The specific pharmacological profile of the 19-norprogestin nomegestrol acetate (NOMAC) is, at least in part, defined by its pattern of binding affinities to the different steroid hormone receptors. In the present study, its affinity to the progesterone receptor (PgR), the androgen receptor (AR) and the estrogen receptor (ER) was re-evaluated and compared to those obtained for progesterone (P) and several progestins. The characteristics of binding to the PgR in rat uterus were determined and Ki were found to be roughly similar with 22.8 and 34.3 nM for NOMAC and P, respectively. The binding characteristics of 3H-NOMAC were also determined and compared to that of 3H-ORG2058 with Kd of 5 and 0.6 nM, respectively for rat uterus and 4 and 3 nM, respectively for human T47-D cells. Structure-affinity and -activity relationships were studied on a variety of compounds related to NOMAC in order to assess its specificity as a progestin. The effects of NOMAC on the binding of androgen to the AR were investigated, using rat ventral prostate as target model. Contrary to what was observed for MPA, the RBA of NOMAC was found to decline with time, showing anti-androgenic rather than androgenic potential, a result that was confirmed in vivo. Regarding the ER, since none of the progestins were able to compete with estrogen for binding in rat uterus as well as in Ishikawa cells, the induction of alkaline phosphatase activity (APase) was used as an estrogen-specific response. It confirmed the intrinsic estrogenicity of progestins derived from 19-nor-testosterone (19NT), norethisterone acetate (NETA), levonorgestrel (LNG) or norgestimate (NGM) and others. In contrast, all P and 19-norP derivatives remained inactive. Finally, to complete this overview of NOMAC at the sex steroid receptor levels, the lack of estrogenic or estrogenic-like activity was checked out in different in vitro models. Data from this study have demonstrated that NOMAC is a progestin that has greater steroid receptor selectivity compared to MPA or some other synthetic progestins. It may provide a better pharmacological profile than those progestins currently in use in HRT and OC.

Animals↗
PubMed2003

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Female↗
PubMed2003

Differential effects of progestins on breast tissue enzymes.

There is substantial evidence that mammary cancer tissue contains all the enzymes responsible for the local biosynthesis of estradiol (E2) from circulating precursors. Two principal pathways are implicated in the final steps of E2 formation in breast cancer tissue: the 'aromatase pathway' that transforms androgens into estrogens and the 'sulfatase pathway' that converts estrone sulfate (E1S) into estrone (E1) via estrone sulfatase. The final step is the conversion of weak E1 to potent biologically active E2 via reductive 17beta-hydroxysteroid dehydrogenase type 1 activity. It is also well established that steroid sulfotransferases, which convert estrogens into their sulfates, are present in breast cancer tissues. One of the possible means of blocking E2 effects in breast cancer is to use anti-estrogens, which act by binding to the estrogen receptor (ER). Another option is to block E2 using anti-enzymes (anti-sulfatase, anti-aromatase, or anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD). Various progestins (e.g. promegestone, nomegestrol acetate, medrogestone, 17-deacetyl norgestimate, dydrogesterone and its 20-dihydro derivative), as well as tibolone and its metabolites, have been shown to inhibit estrone sulfatase and 17beta-hydroxysteroid dehydrogenase. Some progestins and tibolone can also stimulate sulfotransferase activity. These various progestins may therefore provide a new option for the treatment of breast cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Pharmacological profile of progestins.

The synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several new progestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17alpha-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. The later exerts anti-mineralocorticoid effects. This property leads to a decreased salt and water retention and a lowering in blood pressure in users of pills containing this progestin. The 19-norprogesterone derivatives appear more specifically progestational and do not possess any androgenic, estrogenic or glucocorticoid activity. They are referred to as "pure" progestational molecules as they bind almost exclusively to the progesterone receptor (PR) and do not interfere with the other steroid receptor. This category includes, trimegestone, nomegestrol acetate and Nestorone is not active orally but proved to be a potent anti-ovulatory agent when given in implants, vaginal rings or percutaneous gel. Non-androgenic progestins would appear neutral on metabolic factors and on the vessels and would have the advantage of avoiding acnea. Progestins with antiandrogenic properties may also be used for the treatment of women with preexisting androgen related conditions. The progestins available for therapy exhibit profound differences according to their structure or metabolites and it is inappropriate to consider the various effects of the old and new molecules as class-effects.

Estrogen Replacement Therapy↗
PubMed2006

Comparison of fundamental voice frequency between menopausal women and women at menacme.

OBJECTIVE: To analyze comparatively the speaking fundamental frequency (F0) between women at menacme and women in the climacterium taking or not hormonal replacement therapy. METHODS: A controlled transverse study was conducted on 45 women divided into three groups of 15 women each: Group A (women aged 20-40 years with regular menstrual cycles taking no hormonal contraceptives), Group B (women aged 45-60 years with a duration of menopause of at least 2 years taking 1mg estradiol valerate +90 microg norgestimate per day in a continuous treatment scheme lasting at least 6 months), and Group C (women aged 45-60 years with a duration of menopause of at least 2 years taking no HRT for at least 6 months). The mean age for Groups A, B and C was 30.3, 54.5 and 56.5 years, respectively. The groups were analyzed comparatively regarding F0 values for the sustained vowels /e/ and /i/. RESULTS: Mean F0 for the sustained vowels /e/ and /i/ were 215.97 and 229.89 Hz, 206.21 and 221.79 Hz, 200.71 and 212.79 Hz for Groups A, B and C, respectively, with no significant differences between groups. CONCLUSIONS: Although there is evidence of a probable modulating effect of sex steroids on the larynx, in the present study no significant differences in speaking voice were observed regarding menopause or the use of HRT. The absence of such differences observed in F0 does not necessarily mean that there is no difference in vocal quality between these groups since F0 represents only a vocal parameter.

Adult↗
PubMed1995

Androgens and women's health: genetic and epidemiologic aspects of lipid metabolism.

Lipoprotein metabolism may be viewed as a process whereby large, triglyceride-carrying particles from the intestine and liver are broken down into smaller cholesterol-enriched lipoprotein particles. In the process, triglyceride is transported from the intestine and liver to adipose and other storage tissues. Androgen appears to affect lipoprotein metabolism in a number of ways. These include: increasing the activity of lipoprotein lipase and hepatic triglyceride lipase, resulting in higher levels of triglyceride in adipose tissue and a drop in total circulating high-density lipoprotein levels, respectively, and decreasing catabolic removal of low-density lipoproteins from circulating plasma. In pre- and postmenopausal women, androgen progestins in some oral contraceptives, especially the older 19-nortestosterone derivatives such as norgestrel, lower high-density lipoprotein and raise low-density lipoprotein levels. Newer 19-nortestosterone derivatives, such as desogestrel and norgestimate, have a lesser effect on circulating lipoproteins. Nonoral androgenic progestins (e.g., subcutaneous norgestrel) have little effect on circulating lipids, however, which indicates the significance of the "first pass" through the liver for oral agents. The effects of androgens on atherogenesis are largely unexplored, although preliminary studies indicate that they may promote the atherogenic process.

Androgens↗
PubMed1995

The androgenicity of progestins.

All steroid hormones are structurally similar, but relatively minor differences cause profound alterations in biochemical activity. The 21-carbon series (pregnane nucleus) includes the corticoids and the true progestins (e.g., medroxyprogesterone acetate). The 19-carbon series (androstane nucleus) includes all the androgens, among them the progestins used in most oral and parenteral contraceptives. The removal of carbon 19 from testosterone changes the major hormonal effect from androgenic to progestogenic, but these "19-nor" steroids retain varying degrees of androgenic activity. (They can also have limited estrogenic activity, but this is insignificant at the low doses used for contraception.) Some of the 19-nortestosterone progestins are metabolized to other compounds (e.g., norethynodrel, ethynodiol diacetate, and lynestrenol to norethindrone), and some (levonorgestrel, desogestrel) are active unchanged. The lingering androgenic effects of 19-nor progestins are dose-related, opposed by estrogen, and are manifested metabolically (e.g., glucose tolerance, lipoprotein synthesis) and symptomatically (e.g., acne, weight gain). The effect of 19-nortestosterones on lipoproteins prompted the development of less androgenic compounds, but the obvious benefit of the new progestins (desogestrel, gestodene, norgestimate) is a reduction in the symptoms associated with the androgenicity of the older compounds. Mitigation of androgenic effects on lipoprotein and carbohydrate metabolism could have long-term benefits, especially for women who are at risk of arteriosclerotic vascular disease; however, these effects remain to be epidemiologically demonstrated.

Androgens↗