Oral Administration Of Progesterone Research Articles

Administration of dutasteride in animal models of retinitis pigmentosa

AbstractPurpose: Retinitis pigmentosa (RP) describes a large group of hereditary retinopathies. It mainly affects the rods. However, once the rods have degenerated, the cones, also die, leading to complete blindness. Although, the mutations that cause RP have been identified in different genes, the mechanisms that cause the death of photoreceptor cells are still unknown. Gonadal hormones may play a protective role in RP. Our research group has shown that oral administration of progesterone to RP mice significantly conserves the number of photoreceptors. 5α‐reductase inhibitors (such as dutasteride (DUT)) are approved treatments for androgenic alopecia. Modulation or inhibition of 5α‐reductase activity increases the levels of the neuroprotective steroid progesterone and 17β‐estradiol. The purpose of this study was to administer DUT to RP mice. This may be another form of increasing progesterone levels in the retina and therefore, may be neuroprotective.Methods: Animals were treated in accordance with the ARVO statement for the use of animals. rds mice were treated intraperitoneally with DUT and euthanized on day 21. Haematoxylin–eosin, cell death, and rod and cone immunohistochemistry were performed to determine if DUT was able to delay photoreceptor death. Immunohistochemical techniques were used to study changes in retinal microglia (Iba‐1) and macroglial cells. Neuronal nitric oxide synthase (nNOS) was also quantified.Results: DUT increased photoreceptor survival in rds mice. An increase in iba‐1 positive cells was found in rds retinas and DUT normalized the number, migration and the length and number of branches in these cells. DUT decreased GFAP (glial fibrillar acid protein) expression. We have also observed a slightly increase in nNOS expression in rds mice. DUT administration was also able to decrease nNOS expression.Conclusions: DUT may be used to improve cell survival, to ameliorate retinal micro and macroglial activation as well as alterations in nNOS in RP.

Stress-protective effects of micronized progesterone in treatment of anxiety disorders in pregnant women after in vitro fertilisation

Aim. To study a stress-protective efficacy of micronized progesterone (MP) in pregnant women with anxiety disorders after in vitro fertilisation (IVF).
 Materials and methods. We conducted a prospective, comparative open-label randomized trial in two IVF-clinics. A total of 98 pregnant women after IVF with anxiety disorders were recruited at the 9th week of pregnancy. Progesterone supplementation after IVF for luteal phase support was administered out until 9 weeks gestation. Then, after randomization, group 1 (n=35) received 400 mg per day of MP vaginally, group 2 (n=33) received 400 mg of MP orally, group 3 (n=30) was comparative for the other groups. The duration of progesterone treatment was 12 weeks. The Spielberger State Trait Anxiety Inventory (STAI), the Montgomerysberg depression rating scale (MADRS), Hospital Anxiety and Depression Scale (HADS), and the Epworth Sleepiness Questionnaires (ESQ) were used to compare maternal mood at 9 weeks (day of randomization) after delivery and at 283, 565, 847 days after randomization.
 Results. The mean STAI sumscore in MP-groups was significantly lower than in group 3 starting from day 565 and continued until the end of the study. There were no significant differences between vaginal and oral administration of progesterone. There were no significant differences between the mean sumscores when questioning on the HADS, MADRS and ESQ.
 Conclusion. Prolonged use of MP in pregnant women with anxiety disorders led to the prevention of manifestations of an increase in anxiety and depression. The stress-protective and neuromodulating properties of MP can determine additional indications for its prolonged administration in women with anxiety disorders and/or premorbid history.

Effect of copolymer composition on particle morphology and release behavior in vitro using progesterone

This study was aimed at improving dissolution rate and sustained release of progesterone by varying copolymer composition and polymer: drug ratio of PLGA. Drug-loaded particles were prepared using electrohydrodynamic atomization. The effects of polymer: drug ratio and copolymer composition on particle properties and in vitro drug-release profile were investigated. The physical form of the generated particles was determined via X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR). Drug release in vitro was found to be dependent on copolymer composition, where the release rate increased with decreased lactide content of PLGA. Particles produced with solutions of copolymer (75:25) had elongated shapes. In general, the obtained results indicated that the prepared microparticles were ideal carriers for oral administration of progesterone offering great potential to improve the dissolution rate of drugs that suffer from low aqueous solubility.

Sleep after intranasal progesterone vs. zolpidem and placebo in postmenopausal women – A randomized, double-blind cross over study

ContextThe loss of progesterone during menopause is linked to sleep complaints of the affected women. Previously we demonstrated sleep promoting effects of oral progesterone replacement in postmenopausal women. The oral administration of progesterone, however, is compromised by individual differences in bioavailability and metabolism of the steroid. ObjectiveWe compared the sleep-endocrine effects after intranasal progesterone (MPP22), zolpidem and placebo in healthy postmenopausal women. DesignThis was a randomized double-blind cross-over study. SettingGerman monocentric study ParticipantsParticipants were 12 healthy postmenopausal women. InterventionsSubjects received in randomized order four treatments, 2 doses of intranasal progesterone (4.5 mg and 9 mg of MPP22), 10 mg of zolpidem and placebo. Outcome measuresMain outcome were conventional and quantitative sleep-EEG variables. Secondary outcomes were the subjective sleep variables and the sleep related concentrations of cortisol, growth hormone (GH), melatonin and progesterone. ResultsSleep promoting effects were found after the higher dosage of MPP22 and after zolpidem. Zolpidem prompted benzodiazepine-like effects on quantitative sleep EEG as expected, whereas no such changes were found after the two dosages of MP22. Nocturnal progesterone levels increased after 9.0 mg MPP22. No other changes of hormone secretion were found. ConclusionsOur study shows sleep promoting effects after intranasal progesterone. The spectral signature of intranasal progesterone did not resemble the sleep-EEG alterations induced by GABA active compounds. Progesterone levels were elevated after 9.0 mg MPP22. No other endocrine effects were observed.

Fatty alcohol containing nanostructured lipid carrier (NLC) for progesterone oral delivery: In vitro and ex vivo studies

This study aims to overcome most of the obstacles that face oral administration of progesterone. Fatty alcohols (cetyl, cetostearyl and 1:1 mixture) containing NLCs were thought to be one of the most relevant systems based on progesterone drawbacks as acid sensitivity and poor solubility. Formulations were prepared characterized for physicochemical evaluation, in vitro release, in vitro stability in gastric fluid, short term stability, interaction possibility and ex vivo permeation studies. The results showed nanorange particle size with major influence of fatty alcohol concentration. In vitro stability in gastric fluid and release results suggested protection of formulation from gastric environment with controlling the drug release as a function of fatty alcohol concentration. Infrared and thermal analyses showed interaction among fatty alcohol, stearic acid and progesterone. Ex vivo results showed that formulations significantly (p < 0.05) permeated through duodenum when compared with suspension after 8 h. The results collectively indicated that the cetyl alcohol containing NLC was a potential drug delivery system for oral administration of progesterone.

The effect of warm needling pretreatment for endometrial receptivity of frozen embryo transfer

To explore the effect of warming needling pretreatment for endometrial receptivity before frozen-thawed embryo transfer (FET). Fifty-six repeatedly embryo transfer (ET) failure patients with ultrasound showing follicular phase endometrium of C type, hysteroscopy examination presenting endometritis were randomly assigned into an observation group (25 cases) and a control group (31 cases). The patients in the observation group three months before ET were treated with antibiotics in the menstrual period, warming needle (once a day) at Zhongwan (CV 12), Tianshu (ST 25), Guanyuan (CV 4), Zhongji (CV 3), Zigong (EX-CA 1), Liangqiu (ST 34), Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39) after menstruation until the ovulation stopped, and oral administration of progesterone was applied after ovulation. The patients in the control group three months before ET were treated with antibiotics in the menstrual period, and oral administration of progesterone was applied after ovulation. Continuous three menstrual periods were carried out for the both groups. The changes of endometrial thickness, type and endometrial blood flow and the outcome of FET were observed. Endometrial morphology and blood flow were improved after treatment in the two groups (all P<0.01), with better results in the observation group (both P<0.01). The embryo transplantation rate and pregnancy rate in the observation group were higher than those in the control group (both P<0.01), and the early abortion rate decreased (P<0.01). Warm needling may improve endometrial receptivity, embryo transplantation rate and pregnancy rate and decrease early abortion rate by regulating endometrial morphology and blood flow.

Influence of Oral Progesterone Administration on Drug-Induced QT Interval Lengthening: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

We tested the hypothesis that oral progesterone administration attenuates drug-induced QT interval lengthening. Evidence from preclinical and human investigations suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. In this prospective, double-blind, crossover study, 19 healthy female volunteers (21-40 years) were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 49 days). On day 7, ibutilide 0.003 mg/kg was infused over 10 minutes, after which QT intervals were recorded and blood samples collected for 12 hours. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QTcI). Fifteen subjects completed all study phases. Maximum serum ibutilide concentrations in the progesterone and placebo phases were similar (1247±770 vs 1172±709 pg/mL, p=0.43). Serum progesterone concentrations were higher during the progesterone phase (16.2±11.0 vs 1.2±1.0 ng/mL, p<0.0001), while serum estradiol concentrations in the two phases were similar (89.3±62.8 vs 71.8±31.7 pg/mL, p=0.36). Pre-ibutilide lead II QTcI was significantly lower in the progesterone phase (412±15 vs 419±14 ms, p=0.04). Maximum ibutilide-associated QTcI (443±17 vs 458±19 ms, p=0.003), maximum percent increase in QTcI from pretreatment value (7.5±2.4 vs 9.3±3.4%, p=0.02) and area under the effect (QTcI) curve during the first hour post-ibutilide (497±13 vs 510±16 ms-hr, p=0.002) were lower during the progesterone phase. Progesterone-associated adverse effects included fatigue/malaise and vertigo. Oral progesterone administration attenuates drug-induced QTcI lengthening.

Effect of different luteal support schemes on clinical outcome in frozen-thawed embryos transfer cycles

Objective: To evaluate the clinical outcome of frozen-thawed embryo transfer (FET) when using different luteal support schemes. Study Design: Retrospective analysis of FET cycles was performed from June 2013 and December 2013. Infertile women, who underwent FET cycles utilizing embryos cryopreserved on day 3 post-insemination following an initial fresh IVF cycle. Patients were divided into three groups according to the luteal support scheme. Grade A (oral administration of progesterone, n=156), Group B (vaginal administration of progesterone, n=345), Group C (dissolved progesterone in oil with intramuscular infection, n=885), and group C wasdivided into two subgroups according to with (subgroup C1, n=521) or without (subgroup C2 ,n=364) human chorionic gonadotrophin (hCG) injected intramuscularly. The authors compared patients' characteristics and the pregnancy outcomes of each group. Results: There was no difference in the patient characteristics of each group. There was no difference in the implantation rate or clinical and ongoing pregnancy rate among oral, vaginal, and intramuscular progesterone groups. The abortion and ectopic pregnancy rates were not significantly different among the three groups. Conclusion: Oral progesterone in the FET cycles is convenient and has similar pregnancy outcomes compared with intramuscular or vaginal administration.

Neuroprotective actions of progesterone in an in vivo model of retinitis pigmentosa

Progesterone has been shown to have neuroprotective effects in experimental acute brain injury models, but little is known about the effects of steroid sex hormones in models of retinitis pigmentosa (RP). The aim of this study was to asses whether progesterone had a protective effect in one animal model of RP (the rd1 mice), and whether its action was due at least in part, to its ability to reduce free radical damage or to increase antioxidant defences.Rd1 and wild type (wt) mice received an oral administration of 100mg/kg body/weight of progesterone on alternate days starting at postnatal day 7 (PN7) and were sacrificed at different postnatal days.Our results show that progesterone decreases cell death, as the number of TUNEL-positive cells were decreased in the ONL of the retina from treated rd1 mice. At PN15, treatment with progesterone increased values of ERG b-wave amplitude (p<0,5) when compared with untreated mice. Progesterone also decreased the observed gliosis in RP, though this effect was transient.Treatment with progesterone significantly reduced retinal glutamate concentrations at PN15 and PN17. To clarify the mechanism by which progesterone is able to decrease retinal glutamate concentration, we examined expression levels of glutamine synthase (GS). Our results showed a significant increase in GS in rd1 treated retinas at PN13.Treatment with progesterone, significantly increase not only GSH but also oxidized glutathione retinal concentrations, probably because progesterone is able to partially increase glutamate cysteine ligase c subunit (GCLC) at PN15 and PN17 (p<0,05).In summary, our results demonstrate that oral administration of progesterone appears to act on multiple levels to delay photoreceptor death in this model of RP.

Patient?s Preferences for Management Options in Relation to Preterm Birth

To explore pregnant women’s preferences regarding cervical length measurement by ultrasound and treatment with progesterone in relation to preterm birth prevention we performed a discrete choice experiment. Four hospitals, four ultrasound centers and ten midwifery practices spread over the country participated in this study and distributed questionnaires among pregnant women between 15-36 weeks of gestation. Each questionnaire contained 16 choice sets with two screening or treatment options and one opt-out ‘no screening or treatment’ option. Women were asked to consider the following screening/treatment options 1) transvaginal or abdominal cervical length measurement, 2) vaginal or oral administration of progesterone, 3) short-term health risk and 4) long-term health risk for the child. The relative importance of the choices and trade-offs patients were willing to make were analyzed with panel-based mixed logit regression in STATA. Of the 156 questionnaires that were actually handed out, 138 were returned. Overall most respondents made trade-offs between attributes and all screening/treatment characteristics proved important in their decision making. Transvaginal cervical length measurements were not preferred (p=0.01) and was traded only in exchange for an absolute decrease of 6.5% (95% CI 2.6 – 10.4) in long-term neonatal complication rate. Previous experience with adverse neonatal outcome affected the preferences of the women.

Abstract 18740: Influence of Oral Progesterone Administration on QT Interval Response to Ikr Inhibition

Introduction: Evidence from pre-clinical and human studies suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Hypothesis: Oral progesterone administration attenuates QT interval response to I Kr inhibition. Methods: In this prospective, double-blind, crossover study, 15 healthy female volunteers ages 21-40 years were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 52 days). On day 7, a low dose of ibutilide (0.003 mg/kg) was infused over 10 minutes, after which QT intervals were recorded and blood samples serially collected for 12 hours post-infusion. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QT c I). Results: There was no significant difference in maximum serum ibutilide concentrations between the progesterone and placebo phases. (1291±910 vs 1328±718 pg/mL, p=0.87). ECG data are reported from lead II; results are similar from leads V 1 and V 5 . There was no significant difference in pre-ibutilide QT c I between the progesterone and placebo phases (Table). Maximum ibutilide-associated QT c I, maximum % change in QT c I, and % change in area under the effect (QT c I) curve during the first hour following ibutilide administration (AUEC 0-1 , s-hr) were significantly lower during the progesterone phase. Progesterone-associated adverse effects were mild, predominantly fatigue/general malaise. Ibutilide-associated adverse effects during the progesterone and placebo phases included bradycardia [3/15 (20%) vs 2/15 (13%)], burning at infusion site [1/15 (7%) vs 1/15 (7%)], and transient (&lt; 1 minute) Bazett’s-corrected QT c &gt; 500 ms [0/15 vs 1/15 (7%). Conclusions: Oral progesterone administration attenuates QT c I lengthening associated with I Kr inhibition

Differential Sleep-Wake Sensitivity of Gonadotropin-Releasing Hormone Secretion to Progesterone Inhibition in Early Pubertal Girls

Context: Early pubertal luteinizing hormone (LH), and by inference gonadotropin-releasing hormone (GnRH), pulse secretion is marked by high nocturnal but low daytime frequency; however, the underlying mechanisms remain unclear. Plasma concentrations of progesterone, the major regulator of GnRH frequency in women, increase in the early morning in early pubertal girls and may help slow daytime GnRH frequency. Objective: To evaluate the effect of progesterone on LH pulse frequency in early to mid-pubertal girls. Design: Controlled interventional study. Setting: General clinical research center. Participants: Eighteen non-obese, non-hyperandrogenemic Tanner 1–3 girls. Intervention: Twelve-hour (19:00–07:00 h) blood sampling with or without oral progesterone administration (25–50 mg at 16:00 and 20:00 h). Main Outcome Measure: LH pulse frequency. Results: Girls receiving progesterone (n = 5) exhibited lower 12-hour LH pulse frequency than controls (n = 13), but this difference was not statistically significant (average interpulse intervals 196.0 ± 61.9 and 160.4 ± 67.1 min, respectively; p = 0.2793). In contrast to controls, however, girls receiving progesterone exhibited no LH pulses during waking hours (19:00–23:00 h; estimated interpulse interval 326.0 ± 52.7 vs. 212.0 ± 120.9 min; p = 0.0376), while nighttime (23:00–07:00 h) interpulse intervals were similar (174.8 ± 62.0 vs. 167.5 ± 76.9 min, respectively; p = 0.7750). Conclusions: Exogenous progesterone acutely suppressed daytime, but not nocturnal, LH pulse frequency in early to mid-pubertal girls, suggesting that GnRH pulse frequency is differentially regulated by progesterone depending on sleep status.

Short-term oral progesterone administration antagonizes the effect of transdermal estradiol on endothelium-dependent vasodilation in young healthy women

Very few studies have explored the cardiovascular effects of progesterone in premenopausal women. This study aimed to examine the short-term effects of oral progesterone alone, transdermal estrogen alone, and progesterone and estrogen combined on flow-mediated dilation (FMD) in healthy reproductive-aged women. We suppressed endogenous estrogens and progesterone in 17 premenopausal women for 10-12 days using a gonadotropin-releasing hormone antagonist. On day 4 (hormone suppression condition), subjects were tested (n = 17) and were then supplemented with either 200 mg micronized progesterone (n = 8) orally or 0.1 mg estradiol (n = 9) transdermally per day. On day 7 (progesterone-first or estradiol-first condition), subjects were tested and began supplementation with both hormones (n = 17) and were tested again on day 10 (combined hormone condition). FMD of the brachial artery was assessed using B-mode arterial ultrasound, combined with synchronized Doppler analysis. As a result, significant differences in FMD were observed between hormone suppression (7.85 ± 1.06%) and estrogen-first conditions (10.14 ± 1.40%; P < 0.05). The estradiol-induced increase was abolished when oral progesterone was also supplemented (6.27 ± 0.96%). In contrast, we observed a trend toward a decrease in FMD with unopposed progesterone administration, but no statistically significant differences were found between the progesterone-first (6.66 ± 1.23%), hormone suppression (7.80 ± 1.23%), and combined hormone conditions (7.40 ± 1.29%). In conclusion, these data suggest that short-term oral micronized progesterone administration antagonizes the beneficial effect of transdermal estradiol on FMD.

The effects of oral micronized progesterone on smoked cocaine self-administration in women

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers ( N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a “sample” dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.

Comparison of the pharmacokinetics of Crinone 8% administered vaginally versus Prometrium administered orally in postmenopausal women

Objective: Compare the pharmacokinetics of vaginal progesterone gel (Crinone 8%, 90 mg) with that of oral progesterone (Prometrium, 100 mg). Design: Open-label, randomized, parallel-group protocol. Setting: Outpatient clinic. Patient(s): Twelve healthy postmenopausal women. Intervention(s): Six subjects each were randomized to receive progesterone, which was administered either as 90 mg of progesterone gel (Crinone 8%) given vaginally or 100 mg progesterone in a capsule (Prometrium) given orally. Main Outcome Measurement(s): Serum progesterone levels were measured by both radioimmunoassay (RIA) and liquid chromatography-mass spectrometry (LC-MS). Result(s): Progesterone given vaginally resulted in greater bioavailability with less relative variability in absorption than oral progesterone (mean AUC 0–24 = 1.48 ± 0.16 ng · h/mL per milligram vs. 0.035 ± 0.0052 ng · h/mL per milligram). Mean C max for oral progesterone was much lower than that of vaginal progesterone (i.e., 2.20 ± 3.06 ng/mL vs. 10.51 ± 0.46 ng/mL). Mean T max occurred earlier for oral progesterone than for Crinone (1.00 ± 0.41 hours vs. 7.67 ± 3.67 hours). Radioimmunoassay is inappropriate for determining serum progesterone levels after oral administration, because it provided erroneously high values that were approximately eightfold higher than those obtained with LC-MS. Conclusion(s): Crinone (progesterone gel) given vaginally results in greater bioavailability with less relative variability than oral progesterone, thus providing more reliable delivery of progesterone, compared with oral progesterone. Measuring circulating progesterone with use of direct RIA is not appropriate after oral progesterone administration.

Positively Charged Self-Emulsifying Oil Formulation for Improving Oral Bioavailability of Progesterone

A self-emulsifying oil formulation (SEOF) comprised of Tween 80, benzyl alcohol (BA), ethyl oleate (EO), and oleylamine (OA), able to produce positively charged submicron emulsions upon aqueous or buffer dilution, was developed and characterized. The positive charge of the formulation was attributed to the localization of the cationic lipid, OA, at the oil/water interface of the diluted SEOFs. Binary phase diagram analysis of the basic lipophilic system showed that the SEOF elicited progressive inverse phase behavior under continuous aqueous phase dilution. At infinite dilution fine submicron o/w emulsions were formed only when BA concentrations did not exceed 50% in the formulation. The self-emulsification process was not markedly affected by the variation in pH over the entire physiological range. The neurotoxic effects observed in acute toxicity studies with the concentrated emulsion containing 3% BA obtained from the dilution of the SEOF vehicle were attributed to the BA since a simple aqueous solution at the same BA dose caused similar adverse effects. However, no toxic effects were noticed when the dose administered was 30 times the potential dose that could probably be administered to humans. Comparative oral bioavailability studies in young female rats using several different liquid dosage forms of progesterone indicated that of those studied, only the positively charged SEOF could be considered a potential effective dosage form for oral administration of progesterone since it elicited the highest and most satisfactory absorption profile.

Cocaine, AIDS, and intravenous drug use : edited by Samuel R. Friedman and Douglas S. Lipton Harrington Park Press, an imprint of The Haworth Press, Inc. (10 Alice Street, Binghamton, New York 13904-1580), 1991, 124 pp., softcover—$8.95.

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a “sample” dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.

Absorption of oral progesterone is influenced by vehicle and particle size

The oral route of progesterone administration has long been considered impractical because of poor absorption and short biologic half-life. Recent reports suggest that micronization of progesterone enhances absorption and increases serum and tissue levels of progesterone. This study checks serum progesterone levels before and 0.5, 1, 2, 3, 4, and 6 hours after oral administration of 200 mg of progesterone in seven subjects. Progesterone was plain milled, micronized, plain milled in oil, micronized in oil, or micronized in enteric-coated capsules. All patients exhibited a significant increase in serum progesterone levels after oral progesterone administration. Mean peak progesterone levels (30.3 ± 7.0 ng/ml) ( p < 0.005) were achieved with micronized progesterone in oil at 2.0 ± 0.3 ( p < 0.05) hours after administration. Four types of oral progesterone had equivalent mean peak elevations and mean times to peak: plain milled, 9.6 ± 2.5 ng/ml at 4.0 ± 0.5 hours; micronized, 13.2 ± 2.4 ng/ml at 3.2 ± 0.4 hours; plain milled in oil, 11.3 ± 3.0 ng/ml at 4.0 ± 0.5 hours; and micronized in enteric-coated capsules, 11.2 ± 3.0 ng/ml at 4.1 ± 0.7 hours. Contrary to traditional teaching, these data show that significant serum progesterone levels can be achieved by oral administration. Absorption can be significantly improved by the physical characteristics of the progesterone and the vehicle used with oral administration.

Sedative and Hypnotic Effects of Oral Administration of Micronized Progesterone May Be Mediated through Its Metabolites

Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha,20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione) that have been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.

Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites

Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5α-pregnan-3α-ol-20-one, 5β-pregnan-3α-ol-20-one, 5β-pregnan-3α,20β-diol, and 5β-pregnan-3α-ol-11,20-dione) that nave been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.