James A. Simon

The absorption of oral micronized progesterone: the effect of food, dose proportionality, and comparison with intramuscular progesterone*†

OBJECTIVES To examine the effects of food ingestion and administered dose on the absorption of oral micronized P (Utrogestan; Besins-Iscovesco, Paris, France) and to compare the bioavailability of intramuscular versus oral routes of administration. DESIGN Prospective, randomized, open label crossover protocol with 7 days between dosages. SETTING Academic institution. PARTICIPANTS Fifteen normal postmenopausal women. INTERVENTIONS All subjects participated in three separate protocols: [1] micronized P (200 mg) or placebo under fasting or nonfasting conditions once daily for 5 days; [2] micronized P (100, 200, or 300 mg) once daily under fasting conditions for 5 days; and [3] micronized P (200 mg) or intramuscular P (50 mg in oil) administered once daily for 2 days. MAIN OUTCOME MEASURES Serum P concentrations were measured in all groups. RESULTS Concomitant food ingestion increased the area under the serum P concentration versus time curve (AUC0 to 24) and the maximum serum P concentration (Cmax) without affecting time to maximum serum concentration (Tmax) (P < 0.05). Micronized P absorption and elimination were first-order processes and exhibited dose-independent pharmacokinetics between 100 and 300 mg. After intramuscular P, Cmax was higher and Tmax occurred later compared with the oral P preparation. Oral P had lower relative bioavailability (8.6%) than intramuscular P. CONCLUSIONS Absorption of micronized P was enhanced twofold in the presence of food. Both absorption and elimination were dose-independent, dose proportionality being confirmed. Bioavailability of the oral P was approximately 10% compared with intramuscular P.

Differential diagnosis of hot flashes

OBJECTIVE The purpose of this study is to present the physiology and differential diagnosis of hot flashes, other than associated with menopause, in order to facilitate the proper evaluation of symptomatic patients with hot flashes. STUDY DESIGN Literature search using Med-Line computer access. RESULTS Interest in flushing reaction began in historic times. With the rapidly expanding population of women over the age of 45 and prevalence of hot flashes as menopausal symptoms, physicians need to be aware of other medical conditions which may mimic hot flashes. These include flushing due to systemic diseases, carcinoid syndrome, systemic mast cell disease, pheochromocytoma, medullary carcinoma of the thyroid, pancreatic islet-cell tumors, renal cell carcinoma, neurological flushing, emotional flushing, spinal cord injury, flushing reaction related to alcohol and drugs, flushing associated with food additives and eating. CONCLUSION There is a wide variety of disease processes that can cause hot flashes. Knowledge of the nature of these disease processes is necessary for quick recognition of patients with hot flashes who do not respond to estrogen replacement treatment, and to facilitate the proper evaluation of atypical patients.

Factors associated with withdrawal bleeding after administration of oral micronized progesterone in women with secondary amenorrhea

OBJECTIVE To compare two dosages of oral micronized progesterone (P) and placebo for withdrawal bleeding and side effects. DESIGN Prospective, randomized, double-blind. SETTING Academic institution. PARTICIPANTS Out of 190 screened with oligomenorrhea/amenorrhea, 60 who qualified completed the study. INTERVENTIONS A 10-day course of (1) oral micronized P 300 mg, (2) oral micronized P 200 mg, or (3) placebo. MAIN OUTCOME MEASURES Withdrawal bleeding, side effects, and changes in lipids. Endogenous estradiol (E2) concentrations at baseline and P concentrations during treatment were correlated with bleeding response. RESULTS Withdrawal bleeding occurred in 90% of women taking 300 mg, 58% of women taking 200 mg, and 29% of women taking placebo (P less than 0.0002 for 300 mg versus placebo). Side effects occurred similarly among the groups (P = not significant). Lipid concentrations were unchanged. Endogenous E2 and treatment P concentrations were of limited predictive value for withdrawal bleeding. CONCLUSIONS Progesterone 300 mg induced significantly more withdrawal bleeding than placebo, with similar side effects. Bleeding response cannot be predicted reliably from E2 and P concentrations.

Calcium metabolism in postpartum lactation: the effect of estrogen status * †

Postpartum lactation represents a unique state of increased calcium demand in which women are also hyperprolactinemic and hypoestrogenic. This is associated with increased calcium mobilization from bone and bone loss. To better understand the effect of estrogen (E) status on calcium metabolism during lactation, we studied 10 long-term lactating women at 12 weeks postpartum when they were hypoestrogenic and again at 37.4 +/- 3.4 (+/- SD) weeks during the midfollicular phase of their second ovulatory cycle. Urinary and serum markers of calcium metabolism were measured at these intervals. The results revealed that when E was low, osteocalcin and hydroxyproline were increased with a lower circulating parathyroid hormone (PTH) level, whereas reciprocal changes were noted when E was increased. The findings suggest that E status can modulate PTHs ability to mobilize ones stores of calcium.

Effects of vehicle supplementation on total estradiol absorption from a transdermal estradiol delivery system

Objective To evaluate the effects of vehicle supplementation on serum estradiol (E 2 ) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch. Design Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period. Setting Normal human volunteers were studied in an academic research environment. Patients, Participants The subject pool included eight healthy postmenopausal women between 32 and 60 years of age. Interventions In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, an identical patch was worn into which 0.6mL of ethanol was injected on day 3 of use. Main Outcome Measures Serum E 2 levels were measured in both groups. Results Although E 2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E 2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours. Conclusion The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E 2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.

Percutaneous absorption of 17β-estradiol in ovariectomized rhesus monkeys: skin and serum pharmacokinetics *

The skin and serum kinetics of percutaneous estradiol (E2) gel (Oestrogel; Besins-Iscovesco Laboratories, Paris, France) absorption in 11 ovariectomized rhesus monkeys (3 pretreated with diethylstilbestrol [DES]) was studied. The gel (1.5 mg E2) mixed with 7.5 x 10(5) cpm tritiated E2 (3H-E2) was applied to abdominal skin. Serial skin biopsies were taken from the application area and at 1 and 3 cm beyond, as well as from perineum and dorsal skin; and radioactivity measured to estimate tissue levels of E2 derived from percutaneous delivery. Simultaneous femoral serum samples were taken for RIA of E2. Skin 3H-E2 reached a peak at approximately 60 minutes, which was sustained for about 10 hours. Lateral diffusion of the radiolabeled E2 was limited to about 1 cm. Serum E2 levels reached a peak at 60 minutes and remained elevated for 20 hours after a single application. A strong correlation existed between skin and serum E2 levels: r = 0.828. DES did not modify the E2 skin absorption kinetics, but in 2 of 3 monkeys DES reduced the E2 serum levels, suggesting an effect after skin absorption. We conclude that percutaneously delivered E2 manifests a sustained entry into serum. The steady state of continuous release of E2 into circulation derives from a postabsorption skin reservoir of estrogen product.

Detection of the ovulatory-luteinizing hormone surge with an enzyme-linked immunospecific human urinary luteinizing hormone assay: applicability to nonhuman primates.

Heterologous antibodies have frequently been used to develop assays in other species. Human urinary LH kits, widely available for predicting the LH surge, offer a unique opportunity to determine the timing of ovulation and mating in nonhuman primates. We tested three commercially available ovulation predictor kits for utility in two macaque species. Midfollicular, midcycle, and castrate urines and their corresponding serum samples were assessed for LH activity using established RIAs as well as urinary ovulation kits. Macaque LH did not sufficiently cross-react with the human urinary anti-LH antibodies in any of the predictor test kits. Although these kits offer excellent results in predicting ovulation by measurement of urinary LH in humans, they appear not to be applicable for urinary LH detection in rhesus nor cynomolgus macaques.