Wayne S. Maxson

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.

Bioavailability of oral micronized progesterone

Progesterone (P) has not been administered orally because of reportedly poor bioavailability and a rapid clearance rate. Unfortunately, the synthetic derivatives, although orally active, have a number of disadvantages and fail to mimic natural P completely. To investigate the bioavailability and short-term toxicity of oral micronized P, a standardized dose of 200 mg of micronized P was administered to nine healthy postmenopausal women and one male subject. Serial determinations of serum P concentrations demonstrated rapid absorption of P. Peak concentrations of P rose from a negligible baseline level to 17.0 +/- 4.9 ng/ml at an average of 2.8 +/- 0.35 hours after administration. The peak concentrations of P were equivalent to those observed in the midluteal phase in normal control cycles (14.1 +/- 2.7 ng/ml). All subjects exhibited significant elevation of P over baseline levels that persisted for at least 6 hours after the single oral dose and returned to initial levels by 24 hours. There was no significant change in estradiol, follicle-stimulating hormone, luteinizing hormone, cortisol, aldosterone, lipids, or hepatic enzymes during the 24-hour study interval.

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 less than 0.005) were achieved with micronized progesterone in oil at 2.0 +/- 0.3 (p less than 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.

Antiestrogenic effect of clomiphene citrate: correlation with serum estradiol concentrations

The antiestrogenic effect of clomiphene citrate (CC) on cervical mucus was evaluated in women receiving 150 mg CC daily for 5 days. Daily cervical mucus scores and serum estradiol (E2) concentrations were determined in control (n = 25) and CC (n = 24) cycles. E2 concentrations were significantly higher in the CC-treated women (mean +/- standard error of the mean, 1254 +/- 102 pg/ml versus 337 +/- 18 pg/ml, P less than 0.0001). Despite supraphysiologic E2 concentrations, however, cervical mucus scores were significantly reduced in the CC-treated group (P less than 0.01). These data indicate that CC exerts a direct suppressive effect on cervical mucus despite markedly increased E2 concentrations.

The problem of polyspermy in in vitro fertilization

Polyspermy is a potential complication of attempts at in vitro fertilization. Nine polyspermic oocytes were identified among 169 oocytes obtained from 67 cycles stimulated by human menopausal gonadotropin. Cleavage to the 2-, 3-, and 4-cell stage was observed. Four polyspermic oocytes were identified among 85 oocytes obtained from 47 cycles stimulated by clomiphene citrate. Cleavage was not observed. Careful dispersion of cumulus cells at 15 to 18 hours and examination of the oocytes for polyspermy is essential, because the condition may not be apparent at 40 hours from insemination, when normal-appearing cleavage stages may be observed.

A comparison of the CO2 laser and electrocautery on postoperative intraperitoneal adhesion formation in rabbits

The effect of the CO2 laser and microelectrocautery on postoperative intraperitoneal adhesions was examined in 31 female rabbits. Standard injuries were performed and/or repaired with each technique on the uterine peritoneum, the right uterine horn, and the left ovary. The animals were sacrificed 5 weeks later, and the adhesions were graded at each site. No significant differences were found between the two techniques for each site or all sites collectively (P greater than 0.05). The ovary had more extensive adhesions than the other soft tissue site (P less than 0.01) with both techniques. The present study suggests that there is no apparent difference between CO2 laser and conventional microelectrocautery on adhesion formation, and that the ovary seems particularly prone to adhesion formation with either technique.

Prevention of acute pelvic inflammatory disease after hysterosalpingography: Efficacy of doxycycline prophylaxis

In an attempt to minimize the infectious morbidity of hysterosalpingography, the efficacy of oral doxycycline prophylaxis was examined. The records and hysterosalpingograms of 278 consecutive women (group 1) were reviewed to correlate the radiologic findings and the development of acute pelvic inflammatory disease (PID) after hysterosalpingography. Four women (1.4%) developed PID and all four had tubal dilatation. The overall frequency of PID in women with dilated tubes was 4/35 (11%). Subsequently, 56 of 326 women (group 2) with tubal dilatation received oral doxycycline prophylaxis. No cases of PID were observed in the 56 women who had antibiotic prophylaxis (p less than 0.02) or in group 2 as a whole. The study suggests that the risk of infection after hysterosalpingography is very low when nondilated tubes are present (0/398 women of groups 1 and 2). The relative risk of PID in women with peritubal disease or proximal tubal occlusion, although apparently low, remains to be determined. Furthermore, in the highest-risk group of women with dilated tubes, doxycycline prophylaxis was effective in reducing infection after hysterosalpingography.

One ovary or two: differences in ovulation induction, estradiol levels, and follicular development in a program for in vitro fertilization.

The choice of clomiphene citrate (CC) and human menopausal gonadotropin (hMG) protocols for stimulation of ovarian follicular maturation has traditionally not been made with regard to the anatomic status of the pelvis. To evaluate whether hormone production and/or follicular development vary based on the number of ovaries and/or the method of stimulation, 117 cycles were reviewed. Forty-five women received CC, 29 with two ovaries and 16 with one ovary. Seventy-two women received hMG, 50 with two ovaries and 22 with one ovary. Among women receiving CC, those with two ovaries tended to have higher initial estradiol levels and a greater number of large (greater than or equal to 15 mm) follicles. Among women receiving hMG, those with two ovaries tended to have higher estradiol levels, but the number of large follicles (greater than or equal to 15 mm) was similar. With either stimulation protocol, women with two ovaries developed a higher total number of follicles than women with one ovary. The total number of follicles in women with one ovary was similar for hMG and CC stimulations. The number of oocytes recovered at laparoscopy was greater in women with two ovaries who received hMG in comparison with CC, but did not significantly vary between women with one or two ovaries who received CC nor between women with one or two ovaries who received hMG. The number of oocytes was also similar for the women with one ovary regardless of stimulation protocol.

Outcome of progesterone treatment of luteal phase inadequacy

Diagnosis, choice of therapy, and pregnancy outcome were analyzed in 79 women evaluated for luteal phase inadequacy. Criteria for the diagnosis were established, and groups at risk for luteal inadequacy were identified. Treatment choices, tailored to the suspected cause, included progesterone suppositories in 54 women, with 23 pregnancies and 19 deliveries; clomiphene citrate in 6 women, with 2 pregnancies and deliveries; and combined treatment in 7 women, with 5 pregnancies and 4 deliveries. Eight women received no treatment, including three who underwent endometrial biopsy in the cycle of conception and who subsequently delivered. These data suggest that careful diagnosis and the proper choice of treatment are important, and that progesterone supplementation may result in improved pregnancy outcome for patients with infertility and pregnancy wastage who have luteal phase inadequacy.

Efficacy of a Modified Oxidized Cellulose Fabric in the Prevention of Adhesion Formation

A new fabric of regenerated oxidized cellulose (TC-7) was evaluated for the prevention of postoperative adhesions. Standardized injuries were performed on the uterine fundal serosa, the unilateral uterine cornu, and the contralateral ovary in 24 New Zealand rabbits. TC-7 was applied to the injured surfaces in 12 rabbits utilizing a randomized study design. At second-look laparotomy 3 weeks later, adhesions were graded without knowledge of the treatment category in the 22 rabbits surviving the study. There were no statistically significant differences in adhesion formation between treated and control animals at any of the injury sites. No gross or histologic residua of the TC-7 were evident 3 weeks after intraperitoneal application. Further studies will be needed to clarify the clinical role of this new fabric.