Oral contraceptives: mechanism of action, dosing, safety, and efficacy.

The most widely used form of hormonal contraception is the combination oral contraceptive (OC). Combination OCs can be monophasic, providing the same dose of estrogen and progestin daily, or multiphasic, offering varying doses of hormones throughout a 21- or 28-day cycle. The objective of OCs is to suppress ovulation by manipulating events throughout the ovulatory cycle to prevent pregnancy. The progestin and estrogen components of OCs suppress the mid-cycle surge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The overall effect is to decidualize the endometrial bed and suppress mitotic activity. Initial formulations of OCs in the 1960s attempted to mimic the natural cycle; however, providing high doses of estrogen rather than lower doses of combined estrogen and progestin resulted in greater risk of serious adverse events. Today, OCs provide far lower levels of estrogen and progestin. The availability of formulations with drospirenone, a unique progestin pharmacokinetically similar to progestin and similar in structure to spironolactone, should widen usage of OCs. Although OCs are still associated with increased risk in certain patients and are contraindicated in others, they remain effective but require diligent usage.

Improving outcomes through collaboration.

A roundtable was convened to examine the issues surrounding the use of hormonal therapy in the treatment of acne. Obstetrician-gynecologists (OB/ GYNs) and dermatologists often have varying views with regard to the use of oral contraceptives (OCs) and other agents in patients with acne. If polycystic ovary syndrome (PCOS), the most common hormonal cause of acne, has been diagnosed, the use of OCs is not usually disputed. Hormonal evaluation is recommended for certain conditions such as virilization. Although PCOS is often the source of the problem, it is important to rule out a testosterone-producing tumor or an adrenal tumor. It was determined, however, that the perception that OCs cause cervical and breast cancer persists among some dermatologists. Even in women with a family history of breast cancer, OCs do not increase the risk. Nor is cervical cancer related to OC use; rather, it results from human papillomavirus. Thus, patients should be assured that OCs will not increase their risk for either of these cancers. Female patients should be advised to see their gynecologists annually for breast and pelvic examinations and to discuss their concerns surrounding the use of OCs.

A preliminary study of luteal phase versus symptom-onset dosing with escitalopram for premenstrual dysphoric disorder.

OBJECTIVE: This preliminary study compared the efficacy and tolerability of escitalopram administered at symptom onset or throughout the luteal phase in premenstrual dysphoric disorder (PMDD). METHOD: Twenty-seven women meeting DSM-IV criteria for PMDD were randomly assigned in a double-blind manner to luteal phase (N = 13) or symptom-onset (N = 14) dosing of escitalopram (10-20 mg/day) for 3 consecutive menstrual cycles. Participants were enrolled from November 2002 to July 2003, and data collection was completed in December 2003. Symptoms were assessed using the 17-item Penn Daily Symptom Report (DSR), the Clinical Global Impressions-Improvement scale, the Hamilton Rating Scale for Depression, and the Sheehan Disability Scale. Scores were compared using repeated measures analysis of covariance and t statistics. RESULTS: Luteal phase and symptom-onset groups received escitalopram for a mean of 13.5 and 6.0 days, respectively (mean +/- SD dose = 15.2 +/- 5.1 mg/day at the third treatment cycle). Total premenstrual DSR scores significantly improved from baseline (p = .003), with a 57% decrease in the luteal phase group and a 51% decrease in the symptom-onset group. Clinical improvement (DSR score decrease > or = 50% from baseline) was reported by 11 of 13 patients in the luteal phase group and 9 of 14 patients in the symptom-onset group. Symptom severity differentiated the response in the symptom-onset group, with those having more severe symptoms less likely to respond. Symptom severity did not differentiate treatment response to luteal phase dosing. Escitalopram was well tolerated. Adverse events were mild and transient, with only 2 patients discontinuing due to adverse events related to the medication. CONCLUSION: Premenstrual dysphoric disorder improved significantly with either luteal phase or symptom-onset dosing of escitalopram. Women with more severe PMDD may respond better to luteal phase dosing than symptom-onset dosing.

Influences of hormone replacement therapy on olfactory and cognitive function in postmenopausal women.

Olfactory dysfunction can be an early sign of Alzheimer's disease. Since hormone replacement therapy (HRT) may protect against Alzheimer's disease in postmenopausal women, the question arises as to whether it also protects against olfactory dysfunction in such women. A total of three olfactory and 12 neurocognitive tests were administered to 432 healthy postmenopausal women with varied HRT histories. Serum levels of reproductive hormones were obtained for all subjects; APOE-ε4 haplotype was determined for 77 women. National Adult Reading Test and Odor Memory/Discrimination Test scores were positively influenced by HRT. Odor Identification and Odor Memory/Discrimination Test scores were lower for women who scored poorly on a delayed recall test, a surrogate for mild cognitive impairment. The Wechsler Adult Intelligence Scale, Revised, as a Neuropsychological Instrument Spatial Span Backwards Test scores were higher in women receiving estrogen and progestin HRT and directly correlated with serum testosterone levels, the latter implying a positive effect of testosterone on spatial memory. APOE-ε4 was associated with poorer odor threshold test scores. These data suggest that HRT positively influences a limited number of olfactory and cognitive measures during menopause.

Continuous or intermittent dosing with sertraline for patients with severe premenstrual syndrome or premenstrual dysphoric disorder.

OBJECTIVE: The authors compared the efficacy and acceptability of continuous versus intermittent treatment with a selective serotonin reuptake inhibitor in women with severe premenstrual syndrome and determined the effects of postmenstrual symptom severity and depression history as covariates of the treatment response. METHOD: Patients who met symptom criteria and reported impaired functioning after three screening cycles were randomly assigned to three cycles of double-blind, placebo-controlled treatment with continuous (full-cycle dosing) or intermittent (luteal-phase dosing) sertraline. The design was stratified for severity of postmenstrual symptoms and history of major depression. Flexible sertraline dose was 50-100 mg/day. Outcome measures were the Daily Symptom Rating Form score and patient global ratings of functioning. RESULTS: Both sertraline groups improved significantly more than the placebo group as assessed by total premenstrual Daily Symptom Rating Form scores for 3 treatment months. Daily Symptom Rating Form factors that were significantly more improved in the sertraline groups were mood and physical symptoms. Sertraline improvement occurred swiftly in the first month of treatment. Gradual placebo improvement was similar to sertraline in the third month. Subjects with higher postmenstrual symptoms before treatment remained more symptomatic regardless of the dosing regimen. A history of major depression was not associated with treatment response. More sertraline-treated subjects reported improved functioning in the domains of family relationships, social activities, and sexual activity. CONCLUSIONS: Premenstrual dosing does not differ from continuous dosing with sertraline in premenstrual syndrome treatment. Higher levels of postmenstrual symptoms limit treatment response and are important to define in treatment of premenstrual syndrome.

Premenstrual Dysphoric Disorder: Recognition and Treatment.

Premenstrual dysphoric disorder (PMDD) represents the more severe and disabling end of the spectrum of premenstrual syndrome and occurs in an estimated 2% to 9% of menstruating women. The most frequent PMDD symptoms among women seeking treatment consist of anger/irritability, anxiety/tension, feeling tired or lethargic, mood swings, feeling sad or depressed, and increased interpersonal conflicts. Women who develop PMDD appear to have serotonergic dysregulation that may be triggered by cyclic changes in gonadal steroids. The marked increase in the number of well-designed placebo-controlled studies in the past decade has established several selective serotonin reuptake- inhibiting antidepressants as effective first-line treatments for this disorder. Both continuous dosing and intermittent luteal dosing strategies lead to rapid improvement in symptoms and functioning. The present article provides a brief review of current information on the epidemiology, clinical presentation, neurobiology, and treatment of PMDD.

Clinical subtypes of premenstrual syndrome and responses to sertraline treatment.

OBJECTIVE: To estimate response of diagnosis and symptom-based subtypes to sertraline treatment. METHODS: This was a secondary data analysis for women who were diagnosed with premenstrual syndrome (PMS) or premenstrual dysphoric disorder and treated in three National Institutes of Health-supported clinical trials (N=447). Three PMS subtypes were identified based on predominance of psychological, physical, or both symptom types. Scores for each symptom and a total premenstrual score at baseline and endpoint were calculated from daily symptom diaries. Change from baseline after three treated menstrual cycles (or endpoint if sooner) was estimated using linear regression models adjusted for baseline severity. RESULTS: The PMS and premenstrual dysphoric disorder diagnoses improved similarly with sertraline relative to placebo, whereas symptom-based subtypes had differential responses to treatment. The mixed symptom subtype had the strongest response to sertraline relative to placebo (Daily Symptom Rating difference 33.80; 95% confidence interval [CI] 17.16-50.44; P<.001), and the physical symptom subtype had the poorest response to sertraline (Daily Symptom Rating difference 9.50; 95% CI -16.29 to 35.28; P=.470). Results based on clinical improvement (50% decrease from baseline) indicated that 8.3 participants in the mixed symptom subtype, 3.9 in the psychological subtype, and 7.1 in the physical subtype are needed to observe one woman in the subtype who would achieve clinical improvement. CONCLUSION: The PMS and premenstrual dysphoric disorder diagnoses have similar response to sertraline treatment, but symptom-based subtypes have significantly different responses to this treatment. Mixed and psychological symptom subtypes improved whereas the physical symptom subtype did not improve significantly. Identifying the patient's predominant symptoms and their severity is important for individualized treatment and a possible response to a selective serotonin reuptake inhibitor. LEVEL OF EVIDENCE: II.

Time to relapse after short- or long-term treatment of severe premenstrual syndrome with sertraline.

CONTEXT: The duration of treatment after achieving a satisfactory response is unknown in the treatment of premenstrual syndrome. This information is needed in view of the improvement provided by medication vs the adverse effects and costs of drugs. OBJECTIVE: To compare rates of relapse and time to relapse between short- and long-term treatment with sertraline hydrochloride administered in the luteal phase of the menstrual cycle. DESIGN: Eighteen-month survival study with a randomized double-blind switch to placebo after 4 or 12 months of sertraline treatment. SETTING: Academic medical center. PARTICIPANTS: One hundred seventy-four patients with premenstrual syndrome or premenstrual dysphoric disorder. MAIN OUTCOME MEASURE: Relapse, defined as symptoms returning to the entry criterion level as assessed with daily ratings. RESULTS: The relapse rate was 41% during long-term treatment compared with 60% after short-term sertraline therapy, with a median time to relapse of 8 months vs 4 months (hazard ratio, 0.58; 95% confidence interval, 0.34-0.98; P = .04). Patients with severe symptoms at baseline were more likely to experience relapse compared with patients in the lower symptom severity group (hazard ratio, 2.02; 95% confidence interval, 1.18-3.41; P = .01) and were more likely to experience relapse with short-term treatment (P = .03). Duration of treatment did not affect relapse in patients in the lower symptom severity group (P = .50). Patients who demonstrated remission were least likely to experience relapse (hazard ratio, 0.22; 95% confidence interval, 0.10-0.45; P < .001). Further analysis comparing relapse in the first 6 months of placebo treatment in each group yielded similar results. CONCLUSIONS: The relapse rate was significantly greater after short-term treatment compared with long-term treatment. The relapse rate was also high during extended drug treatment. Subjects with severe symptoms at baseline were most likely to experience relapse, and relapse occurred more swiftly regardless of treatment duration. These findings suggest that the severity of symptoms at baseline and symptom remission with treatment should be considered in determining the duration of treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00318773.

Citalopram in PMS patients with prior SSRI treatment failure: a preliminary study.

OBJECTIVES: Evidence shows that the selective serotonin reuptake inhibitors (SSRIs) effectively reduce the symptoms of severe premenstrual syndrome (PMS). A placebo-controlled study of citalopram, the most selective SSRI, demonstrated that half-cycle dosing (luteal phase) was effective for DSM-IV-defined premenstrual dysphoric disorder (PMDD), a severe form of PMS. This study examined the effectiveness of half-cycle dosing of citalopram in PMS patients who did not respond to previous SSRI treatment. METHODS: Seventeen women with no improvement in symptoms after two menstrual cycles on an SSRI were given open-label citalopram (20-40 mg/day). Eleven subjects received half-cycle dosing, and 6 subjects received full-cycle dosing. Scores on the 17-item daily symptom report (DSR) and on each of five DSR symptom clusters were used to measure citalopram efficacy. RESULTS: Total premenstrual DSR scores were significantly improved (p <0.001) in both half-cycle and full-cycle dosing groups. The half-cycle group reported lower DSR scores throughout treatment compared with the full-cycle group, but the difference did not reach statistical significance in this small sample. All DSR factor scores (mood, behavioral, pain, physical symptoms, and appetite) significantly improved. Clinical improvement (>or=50% decrease from baseline DSR) was reported by 76% of the subjects overall. Forty-one percent of the subjects experienced symptom remission, defined as a decrease in symptoms to postmenstrual levels. CONCLUSIONS: These results from a small number of subjects with open-label treatment must be viewed as preliminary but suggest that citalopram treatment is effective for PMS patients who failed previous SSRI treatment.

Male axillary extracts contain pheromones that affect pulsatile secretion of luteinizing hormone and mood in women recipients.

Human underarm secretions, when applied to women recipients, alter the length and timing of the menstrual cycle. These effects are thought to arise from exposure to primer pheromones that are produced in the underarm. Pheromones can affect endocrine (primer) or behavioral (releaser) responses, provide information (signaler), or perhaps even modify emotion or mood (modulator). In this study, we extracted underarm secretions from pads worn by men and placed the extract under the nose of women volunteers while monitoring serum LH and emotion/mood. Pulses of LH are excellent indicators of the release of GnRH from the brain's hypothalamus. In women, the positive influence of GnRH on LH affects the length and timing of the menstrual cycle, which, in turn, affects fertility. Here we show that extracts of male axillary secretions have a direct effect upon LH-pulsing and mood of women. In our subjects, the putative male pheromone(s) advanced the onset of the next peak of LH after its application, reduced tension, and increased relaxation. These results demonstrate that male axillary secretions contain one or more constituents that act as primer and modulator pheromones.

Endometritis does not predict reproductive morbidity after pelvic inflammatory disease.

OBJECTIVE: We investigated the association between endometritis and reproductive morbidity. STUDY DESIGN: Participants were 614 women in the PID Evaluation and Clinical Health (PEACH) Study with pelvic pain, pelvic organ tenderness, and leukorrhea, mucopurulent cervicitis, or untreated cervicitis. We compared women with endometritis (>or=5 neutrophils or >or=2 plasma cells), Neisseria gonorrhoeae or Chlamydia trachomatis upper genital tract infection (UGTI) or both to women without endometritis/UGTI for outcomes of pregnancy, infertility, recurrent pelvic inflammatory disease (PID), and chronic pelvic pain (CPP), adjusting for age, race, education, PID history, and baseline infertility. RESULTS: Endometritis/UGTI was not associated with reduced pregnancy (odds ratio [OR] 0.8, 95% CI 0.6-1.2) or elevated infertility (OR 1.0, 95% CI 0.6-1.6), recurrent PID (OR 0.6, 95% CI 0.4-0.9), or CPP (OR 0.6, 95% CI 0.4-0.9). PEACH participants with and without endometritis/UGTI had higher age- and race-specific pregnancy rates than 1997 national rates. CONCLUSION: Among women with clinically suspected mild-to-moderate PID treated with standard antibiotics, endometritis/UGTI was not associated with reproductive morbidity.

Effectiveness of inpatient and outpatient treatment strategies for women with pelvic inflammatory disease: results from the Pelvic Inflammatory Disease Evaluation and Clinical Health (PEACH) Randomized Trial.

OBJECTIVE: Pelvic inflammatory disease (PID) is a common and morbid intraperitoneal infection. Although most women with pelvic inflammatory disease are treated as outpatients, the effectiveness of this strategy remains unproven. STUDY DESIGN: We enrolled 831 women with clinical signs and symptoms of mild-to-moderate pelvic inflammatory disease into a multicenter randomized clinical trial of inpatient treatment initiated by intravenous cefoxitin and doxycycline versus outpatient treatment that consisted of a single intramuscular injection of cefoxitin and oral doxycycline. Long-term outcomes were pregnancy rate, time to pregnancy, recurrence of pelvic inflammatory disease, chronic pelvic pain, and ectopic pregnancy. RESULTS: Short-term clinical and microbiologic improvement were similar between women randomized to the inpatient and outpatient groups. After a mean follow-up period of 35 months, pregnancy rates were nearly equal (42.0% for outpatients and 41.7% for inpatients). There were also no statistically significant differences between outpatient and inpatient groups in the outcome of time to pregnancy or in the proportion of women with pelvic inflammatory disease recurrence, chronic pelvic pain, or ectopic pregnancy. CONCLUSION: Among women with mild-to-moderate pelvic inflammatory disease, there was no difference in reproductive outcomes between women randomized to inpatient treatment and those randomized to outpatient treatment.