Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Assessment of ethynylestradiol-3-sulfate on coagulation, metabolism, and survival in pigs with traumatic hemorrhage.

BACKGROUND: The beneficial effects of estrogens on survival from hemorrhage have been suggested in some preclinical models. This study investigated the effects of ethynylestradiol-3-sulfate (EE-3-S) on coagulation, metabolism and survival in pigs following traumatic hemorrhage. METHODS: Twenty-six pigs were randomized into: normal saline group (NS, n = 10), EE-3-S group (EE-3, n = 11) groups, and no resuscitation group (NR, n = 5). Femur fracture was performed in each pig's left leg, followed by hemorrhage of 55% of estimated blood volume and a 10-minute shock period. Afterward, pigs were resuscitated with a small volume of either NS alone (4 mL/kg) or EE-3-S with NS (1 mL/kg at concentration of 1 mg/mL, plus NS solution of 3 mL/kg). Pigs in NR group were not resuscitated with any fluid. All pigs were then monitored for 6 hours or until death, with hemodynamics and survival times recorded. Blood samples were taken during the study for measurements of oxygen metabolism (oxygen delivery, extraction, and consumption) and coagulation function (using Rotem with Extem reagents). RESULTS: All baseline measurements were similar among the three groups. In the NS group, femur fracture and hemorrhage immediately reduced mean arterial pressure (MAP, 74 ± 3 mm Hg to 44 ± 4 mm Hg) and increased heart rate (97 ± 5 bpm to 218 ± 14 bpm, both p < 0.05). Similar changes in MAP and heart rate were observed in the EE-3 and NR groups. There were no differences observed in changes of Rotem ® measurements or oxygen metabolism among the groups during the study. At 6 hours, four pigs in NS, four pigs in EE-3-S, and two pigs in the NR group survived to the end of the study. The mean survival times were similar among the NS (212 ± 43 minutes), EE-3 (212 ± 39 minutes), and NR (223 ± 63 minutes) groups ( p = 0.9845). CONCLUSION: Following severe traumatic hemorrhage, hypotensive resuscitation with EE-3-S did not impact coagulation, metabolism, or survival in pigs.

Ethinyl estradiol and 17ß-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment.

The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been ongoing since the introduction of COCs more than 50 years ago. New progestin formulations combined with lower doses of ethinyl estradiol (EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes of COC treatment. Previous attempts to use endogenous 17ß-estradiol (E2) instead of EE were limited primarily by poor cycle control. The recent introduction of E2-based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the pharmacology of EE and E2, including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.

Predictors of noncompliance in an oral contraceptive clinical trial.

BACKGROUND: This analysis was conducted to identify the participant characteristics associated with noncompliance in an oral contraceptive (OC) clinical trial. STUDY DESIGN: We studied ovarian suppression among normal-weight and obese women during the use of levonorgestrel (LNG)-containing combination OCs. Participants underwent twice weekly phlebotomy during the study cycle and received up to $360 for participation. Along with other study assays, we analyzed 903 specimens from 181 women to measure LNG to assess OC compliance. Consistently undetectable LNG levels indicated noncompliance. To evaluate predictors of OC noncompliance during this study, we compared the characteristics of compliant and noncompliant participants using multivariable logistic regression. We assigned each participant to a relative poverty level based on US census data; all other individual characteristics came directly from participant responses during the baseline interview. RESULTS: One hundred eighty-one women completed the study; 31 were noncompliant (17%). In multivariable analyses, poverty level was the strongest predictor of noncompliance. Compared with those women in the quartile with the lowest level of residential poverty, other women were far more likely to be noncompliant, especially women in the quartile with the greatest prevalence of poverty (adjusted odds ratio, 8.4; 95% confidence interval, 1.5-46.1). Additional factors associated with noncompliance were education level less than a bachelor's degree and Hispanic ethnicity. Other demographic and psychometric measures were not associated with compliance. CONCLUSIONS: We found that noncompliance was strongly associated with residential poverty level, an indirect measure of individual income. In the United States, poverty is associated with female obesity, Hispanic ethnicity and low education, which were also associated here with noncompliance. Study compensation may motivate poor individuals to participate in clinical trials for income. Noncompliance in clinical trials, particularly differential noncompliance, jeopardizes study validity.

Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide.

BACKGROUND: The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. STUDY DESIGN: We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose-response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. RESULTS: We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose-response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl estradiol (EE). CONCLUSION: This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition potency and a summary of all preparations currently on the world market, including their regimens and their combinations with EE.

Oral estroprogestin: an alternative low cost therapy for women with postoperative persistent acromegaly?

Oral estrogens reduce GH-induced IGF-1 production and preliminary studies have shown that adjuvant estroprogestin (EP) therapy with octreotide LAR may control disease activity in some female patients who are partially responsive to octreotide LAR. Our aim was to verify if EP alone or in combination with octreotide LAR can achieve remission of acromegaly in selected cases of patients uncontrolled by surgery. Eleven women with persistent active acromegaly following surgery participated in this unblinded open label pilot study. Their mean age was 49.8 ± 4.3 years. Two patients were drug naïve, two patients had stopped octreotide LAR because of intolerance and seven were treated with octreotide LAR. The patients received either EP (EP pill, 20 µg ethinylestradiol, 100 µg levonorgestrel) alone (4 patients) or added to octreotide LAR (7 patients). Fasting GH, IGF-1, glucose, HDL- and LDL-cholesterol, and triglycerides were measured at baseline and at last visit. MRI was controlled at baseline and at last visit. Duration of estrogen treatment was 3.1 ± 0.5 years. Serum IGF-1 levels were normalized in 8/11 patients (73%). Serum GH concentrations did not change significantly during treatment (11.6 ± 5.6 µg/L prior to EP vs 5.5 ± 1.2 µg/L following EP). In patients treated with EP alone, remission was achieved in 2/4 patients (IGF-1 percentages of the upper limit of normal age-matched range (%ULN): 211 ± 40% before EP compared to 95 ± 15% after EP, P = 0.028). In the seven patients treated by EP added to octreotide LAR, remission was achieved in 6 patients (IGF-1%ULN: 158 ± 9% before EP compared to 86 ± 4% after EP, P = 0.0003). Glucose and cholesterol levels were unchanged by EP treatment (data not shown). MRI did not show any evidence of tumour progression with EP in patients who had a tumour remnant. In conclusion, oral estrogen treatment appears to normalize serum IGF-1 concentrations in over 70% of women with acromegaly uncured by surgery irrespective of their sensitivity to octreotide LAR. We suggest that estrogens may be a temporary cost-effective and safe treatment for women with postoperative persistent acromegaly.

Further assessment of 17alpha-ethinyl estradiol as an inhibitor of different human cytochrome P450 forms in vitro.

17alpha-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC(50) (concentration of inhibitor required to decrease activity by 50%) values were obtained with recombinant CYP1A1 (rCYP1A1) [IC(50(total)) = IC(50(free)) = 2.7 microM] and CYP2C19 activity in human liver microsomes (HLM) [IC(50(total)) = 4.4 microM; IC(50(free)) = 2.8 microM]. For rCYP1A1, formal inhibition studies revealed that EE was a competitive inhibitor [K(i(free)) = 1.4 microM]. All the other IC(50) values were greater than 8.0 microM, and the weakest inhibition was observed with CYP1A2 activity in HLM (IC(50(free)) > 39 microM). In agreement, the IC(50) characterizing the inhibition of melatonin (MEL) 6-hydroxylation in human intestine microsomes (CYP1A1-catalyzed) was lower than that of HLM (0.91 versus >40 microM). Because EE is known to affect the pharmacokinetics of CYP2C19 probe drugs, this result raises the possibility that the concentration of EE during first pass may exceed 1000 nM, sufficient to affect CYP1A1 and CYP2C19, with less impact on CYP3A4 and other P450s. The results implicate intestinal CYP1A1, and possibly CYP2C19, as the loci of EE drug interactions with highly extracted drugs like MEL. Overall, it is very difficult to rationalize drug interactions involving EE based on direct inhibition of CYP2B6 (e.g., selegiline) and hepatic CYP1A2 (e.g., MEL, tizanidine, caffeine, and theophylline).

Avaliação da tolerabilidade, aceitabilidade e controle do ciclo em adolescentes usuárias de anticoncepcional hormonal combinado oral de baixa dose com gestodeno e etinilestradiol / Assessment of the tolerability, acceptability and cycle control in tenager users of oral low dose combined hormonal contraceptive with gestodene and ethinylestradiol

OBJETIVO: Os anticoncepcionais hormonais orais vêm sofrendo progressiva redução de dose desde as suasformulações iniciais, sem, no entanto comprometer sua eficácia e com considerável melhora do seu perfil de segurança. Entre jovens adolescentes, a satisfação com essas novas formulações tem sido maior que a de usuárias de outros métodos. Isso é particularmente conveniente, já que nessa faixa etária ocorre a maioria das gestações não-desejadas. O impacto causado por essas gestações e os riscos associados ao alto percentual de abortos justifica o desenvolvimento e a análise de novas formulações contraceptivas em pacientes adolescentes. Nosso objetivo neste estudo foi avaliar a tolerabilidade, aceitabilidade e controle do ciclo de um contraceptivo hormonal oral de baixa dose contendo gestodeno (75 microgramas) e etinilestradiol (20 microgramas), em mulheres adolescentes. MÉTODOS: Este foi um ensaio clínico aberto, não-comparativo e multicêntrico conduzido em pacientes ambulatoriais. A idade das participantes deste estudo variou de 14 a 20 anos. Estatísticas descritivas foram empregadas para a análise do controle do ciclo e segurança. Alterações de peso, estatura, pressão arterial, freqüência cardíaca, dados laboratoriais, duração do ciclo, e sangramento de privação foram avaliados pelo teste t pareado. RESULTADOS: O presente estudo avaliou um número significativo de ciclos (918 ciclos) para permitir uma análise adequada dos sangramentos de privação e intermenstruais na vigência da medicação proposta. Conforme observamos, o emprego da formação GTD75/EE20 ofereceu um bom controle do ciclo, praticamente não alterando o padrão próprio da usuária, prévio ao uso do contraceptivo. CONCLUSÕES: A formulação contraceptiva GTD75/EE20 traz características muito adequadas à sua indicação em adolescentes que, para aceitação e aderência apropriadas, necessitam de um método seguro, com bom controle de ciclo, eficácia contraceptiva, bom controle do peso corporal e baixa incidência de reações adversas

Impaired estrogen-induced negative feedback on gonadotropin secretion in patients with gonadotropin-secreting and nonfunctioning pituitary adenomas.

BACKGROUND: Several in vitro studies suggest that gonadotropin-secreting pituitary adenomas (Gn-omas) and non functioning pituitary adenomas (NFPA) originate from gonadotroph cells. Patients with Gn-oma and NFPA frequently show abnormal gonadotropin response to TRH. The aim of the study was to investigate whether the estrogen-induced negative feedback is operating in either patients with Gn-oma or NFPA. MATERIALS AND METHODS: Serum gonadotropin levels were evaluated at 24 h after ethinylestradiol administration (1 mg per os; EE2 test) in seven patients with a diagnosis of Gn-oma, based on the presence of high follicle-stimulating hormone (FSH) and/or lutenising hormone (LH) levels with normal or high levels of sex steroids, in 22 patients with NFPA with normal or low levels of gonadotropin and sex steroids, and 30 sex- and age-matched healthy subjects. A normal response to EE2 test was arbitrarily defined as a serum LH and FSH decrease of at least 40 and 30% below basal levels. RESULTS: Among patients with Gn-oma, only one had a normal FSH inhibition and another, a normal LH inhibition. Among the 22 patients with NFPA, the EE2 test caused a normal FSH or LH reduction in 10 and 15, respectively, while a normal reduction of both FSH and LH was observed in nine. CONCLUSIONS: The study demonstrates that estrogen-induced negative feedback of gonadotropin secretion is disrupted in almost all patients with Gn-oma and in half of those with NFPA. This defective feedback is reminiscent of the resistance to thyroid hormones and glucocorticoids observed in patients with thyroid-stimulating hormone- (TSH-) and adrenocorticotropic hormone- (ACTH-)secreting adenomas, respectively.

Assessment of oestrogenic potency of chemicals used as growth promoter by in-vitro methods.

Three in-vitro bioassays were used to compare the oestrogenic potency of chemicals used as growth promoter in beef cattle in certain non-European Union countries (17beta-oestradiol, alpha-zearalanol, testosterone, trenbolone, trenbolone acetate, melengestrol acetate) or found as food contaminant such as the mycotoxin zearalenone and some of their metabolites (17alpha-oestradiol, oestrone, 17alpha-epitestosterone, 19-nortestosterone, androstendione, zearalanone, alpha-zearalanol, beta-zearalanol, alpha-zearalenol, beta-zearalenol). The strong oestrogens 17alpha-ethinyl oestradiol and diethylstilboestrol were used as standards. The first bioassay was based on the activation of a reporter gene by oestrogens in recombinant yeast expressing human or rainbow trout oestrogen receptor. In the second bioassay, the vitellogenin gene induction of rainbow trout hepatocyte cultures was used as a biomarker for the exposure to oestrogens. The third bioassay was based on the alkaline phosphatase gene induction by oestrogens in the human endometrial Ishikawa cell line. The assessment of oestrogenic potency of these chemicals clearly demonstrates the strong oestrogenicity of the mycotoxin zearalenone and its metabolites and particularly alpha-zearalenol which was as potent as ethinyl oestradiol and diethylstilboestrol in the human endometrial Ishikawa cell line.

Release of progestin-only emergency contraception.

Progestin-only emergency contraception has been available in a prepackaged product since 1999. In a multicenter randomized trial, the levonorgestrel-only regimen was better tolerated and significantly more effective than the previous standard of care, the Yuzpe regimen. The levonorgestrel-only regimen prevented 85% of unintended pregnancies compared with 57% in the Yuzpe regimen. Emergency contraception is more effective the earlier the treatment begins. With the emergence of specifically prepackaged kits, emergency contraception appears to be more accessible and convenient to providers and to women. However, substantial barriers still exist to women who wish to obtain emergency contraceptive within the recommended initiation of 72 hours after unprotected intercourse. More recent information that emergency contraception is more effective the sooner it is initiated underscores the need for effective educational and distribution strategies.

Effects of oral contraceptives in vaginal cytology.

Many literature studies have shown that long-term use of oral contraceptives (OC) is associated with lack of protection of the epithelium of the uterine cervix. Forty-five patients, from 18 to 35 years old, users of two contraceptive formulations, of different estrogenic concentration, took part in this study as volunteers to evaluate the predisposition of the cervix to pathologies. The results found before OC use were 11% of Chlamydia trachomatis infection and 13% of HPV infection. These pathologies were correctly treated and after 5 months of OC use we found total remission of Chlamydia trachomatis infection and 4% of persistent HPV infection. These data lead us to conclude that the OC studied here interfered very little with the presented pathologic results. The risk factors that we considered relevant were: 1) age group (the patients that presented HPV and C. trachomatis infections were young university students); 2) lifestyle (most patients certified that they did not combine the use of barrier contraceptives with the use of OC); 3) multiple sexual partners; 4) low socioeconomic condition.

Comparative assessment of two low-dose oral contraceptives, Lo-Femenal and Lo-Estrin, in Mexican women.

This trial was designed to determine the differences in effectiveness, clinical acceptability, and one-year discontinuation rates of two low-dose oral contraceptives: Lo-Estrin (norethindrone acetate 1.5 mg plus ethinyl estradiol 0.030 mg) and Lo-Femenal (norgestrel 0.30 mg plus ethinyl estradiol 0.030 mg) in 148 Mexican women. In addition, the effects of both oral contraceptive preparations on blood lipids were prospectively evaluated in a subgroup of 41 women. The results indicated that there were no differences in pregnancy rates, discontinuation or clinical acceptability between the two groups. The lipid changes observed were minimal for the Lo-Femenal subgroup and somewhat greater for the Lo-Estrin group, mainly an increase in serum triglycerides. These changes were interpreted as estrogen induced effects of norethindrone-containing oral contraceptives. Overall, the data indicate that both Lo-Femenal and Lo-Estrin are effective and safe combined oral contraceptives.

Desogestrel and gestodene in oral contraceptives: 12 months' assessment of carbohydrate and lipoprotein metabolism.

We examined the influence on carbohydrate and lipoprotein metabolism of oral contraceptives (OCs) containing two new third-generation progestogens, desogestrel and gestodene. This was a prospective randomized study in which monophasic combinations of 20 micrograms ethinyl estradiol (E2) and 150 micrograms desogestrel or 30 micrograms ethinyl E2 plus 75 micrograms gestodene were administered to 15 and 19 healthy women, respectively. An oral glucose tolerance test including measurement of insulin response was performed before treatment and after 3, 6, and 12 months of treatment. We also determined fasting plasma concentrations of total cholesterol; high-density lipoprotein cholesterol, including the subfractions high-density lipoprotein2 cholesterol and high-density lipoprotein3 cholesterol; low-density lipoprotein cholesterol; very low-density lipoprotein cholesterol; and triglycerides. A transient deterioration of glucose tolerance was observed despite unchanged levels of insulin after treatment with both compounds for 3 months. In both groups plasma levels of triglycerides, very low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol increased significantly after 3 months. After 12 months, a significant increase in the high-density lipoprotein cholesterol/total cholesterol ratio was observed in the ethinyl E2-desogestrel group, and no persistent changes in low-density lipoprotein cholesterol could be demonstrated in any of the groups. Our results indicate that treatment with either compound for 12 months has no effect on carbohydrate or lipoprotein metabolism known to increase the risk of cardiovascular disease.

Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: preliminary results of a double-blind randomized study of the EORTC Breast Cancer Cooperative Group.

We investigated whether estrogenic recruitment could enhance the antitumor effect of chemotherapy in 165 patients with advanced breast cancer, presumably sensitive to hormonal treatments (ER + and/or PgR + lesions). The therapeutic regimen consisted of: (a) estrogenic suppression by aminoglutethimide 1 g/day + hydrocortisone 40 mg/day; surgical castration in premenopausal patients only; (b) FAC (5FU 500 mg/m2; ADM 50 mg/m2; CPA 500 mg/m2) for 3 weeks; (c) following randomization, exactly 24 h prior to chemotherapy, patients had to take 1 tablet of either placebo (PL) or 50 microgram ethinylestradiol (EE2). Tolerance, responses, time to progression and median survival were identical in both groups. Thus, EE2 before chemotherapy did not contribute to the efficacy of this particular therapeutic regimen, which yielded an overall response rate of 64%. We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice, so that this approach remains experimental.

Clinical assessment of treatments for prolonged bleeding in users of Norplant implants.

The effectiveness of three drugs in controlling prolonged bleeding in the first year of NORPLANT implants use was tested. The drugs were levonorgestrel (L-Ng, 0.03 mg twice a day for 20 days), ethinylestradiol (EE, 0.05 mg per day for 20 days) and ibuprofen (Ib, 800 mg three times a day for 5 days) and were given orally. A control group received a placebo (PL, one pill of lactose for 20 days). Treatment should start each time a woman experienced eight consecutive days of bleeding or spotting. The 183 volunteers were not aware of the drug administered. A daily record of bleeding and spotting and of treatment intake was maintained. One-hundred-forty women completed the study period; 60 never used the prescribed treatment. Women treated with the three test drugs had significantly fewer bleeding and spotting days during the treated month and also throughout the study year than women using the placebo. The mean number of bleeding plus spotting days per actually treated subject in the first year was 77, 94, 101 and 129 days for the EE, Ib, L-Ng and PL groups, respectively. The administration of EE might help in the management of prolonged bleeding during the first year of NORPLANT implants use.

Oral contraception and insulin sensitivity: in vivo assessment in normal women and women with previous gestational diabetes.

The sensitivity to insulin (euglycemic clamp technique) was assessed in previous gestational diabetic women (n = 6) and nondiabetic women (n = 6) before and twice during low-dose triphasic oral contraceptive administration (ethinyl estradiol and levonorgestrel) for 6 months. Both groups had normal plasma glucose and insulin levels during oral glucose tolerance tests before and during treatment. In vivo peripheral insulin action was measured during insulin infusion of 40 mU/m2 X min with plasma glucose clamped at fasting levels. Before treatment glucose infusion rates were identical in both groups [1.56 +/- 0.12 (SEM) mmol/m2 X min and 1.51 +/- 0.09 mmol/m2 X min, respectively]. After hormonal treatment for 6 months the amount of glucose infused decreased significantly in the previously gestational diabetic women (1.10 +/- 0.12 mmol/m2 X min, P = 0.01), whereas the decrease was less pronounced in the nondiabetic women (1.30 +/- 0.22 mmol/m2 X min, P = 0.09). The decrease in insulin sensitivity was not sufficient to alter glucose tolerance either in the previous gestational diabetic women nor in the nondiabetic women.

Objective techniques for the assessment of postmenopausal hot flashes.

The present study was undertaken to evaluate objective methods of monitoring postmenopausal hot flashes. Continuous recordings of finger and core temperature and sternal skin conductance were carried out in 8 postmenopausal and 4 premenopausal women. Four postmenopausal patients were studied a second time following 30 days of daily oral administration of ethinyl estradiol 0.05 mg. One hundred twenty flashes were subjectively noted and recorded during 104 hours of study in the postmenopausal women. Eighty-two, 98, and 81% of subjective flashes were associated with changes in finger temperature, skin conductance, and core temperature, respectively. The rate of occurrence and magnitude of changes of physiologic markers were significantly greater (P less than .01) in postmenopausal than premenopausal women. Estrogen replacement therapy not only eliminated the subjective sensations but also significantly reduced (P less than .02) the frequency and magnitude of the changes in physiologic function measured by finger temperature. Measurement of skin conductance changes was the single most sensitive and specific indicator of hot flashes. The simultaneous change of both skin conductance and finger temperature, although less sensitive, was a very specific indicator of a hot flash. These results support the concept that the measurement of physiologic changes can be used to assess objectively the occurrence of this symptom complex.