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Women’s health concerns are generally underrepresented in basic and translational research, but reproductive health in particular has been hampered by a lack of understanding of basic uterine and menstrual physiology. Menstrual health is an integral part of overall health because between menarche and menopause, most women menstruate. Yet for tens of millions of women around the world, menstruation regularly and often catastrophically disrupts their physical, mental, and social well-being. Enhancing our understanding of the underlying phenomena involved in menstruation, abnormal uterine bleeding, and other menstruation-related disorders will move us closer to the goal of personalized care. Furthermore, a deeper mechanistic understanding of menstruation—a fast, scarless healing process in healthy individuals—will likely yield insights into a myriad of other diseases involving regulation of vascular function locally and systemically. We also recognize that many women now delay pregnancy and that there is an increasing desire for fertility and uterine preservation. In September 2018, the Gynecologic Health and Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a 2-day meeting, “Menstruation: Science and Society” with an aim to “identify gaps and opportunities in menstruation science and to raise awareness of the need for more research in this field.” Experts in fields ranging from the evolutionary role of menstruation to basic endometrial biology (including omic analysis of the endometrium, stem cells and tissue engineering of the endometrium, endometrial microbiome, and abnormal uterine bleeding and fibroids) and translational medicine (imaging and sampling modalities, patient-focused analysis of menstrual disorders including abnormal uterine bleeding, smart technologies or applications and mobile health platforms) to societal challenges in health literacy and dissemination frameworks across different economic and cultural landscapes shared current state-of-the-art and future vision, incorporating the patient voice at the launch of the meeting. Here, we provide an enhanced meeting report with extensive up-to-date (as of submission) context, capturing the spectrum from how the basic processes of menstruation commence in response to progesterone withdrawal, through the role of tissue-resident and circulating stem and progenitor cells in monthly regeneration—and current gaps in knowledge on how dysregulation leads to abnormal uterine bleeding and other menstruation-related disorders such as adenomyosis, endometriosis, and fibroids—to the clinical challenges in diagnostics, treatment, and patient and societal education. We conclude with an overview of how the global agenda concerning menstruation, and specifically menstrual health and hygiene, are gaining momentum, ranging from increasing investment in addressing menstruation-related barriers facing girls in schools in low- to middle-income countries to the more recent “menstrual equity” and “period poverty” movements spreading across high-income countries.

Background Changes in menstrual bleeding concern many users of the 52 mg Levonorgestrel Intrauterine System. Prescribing information for Levonorgestrel Intrauterine System devices describe an overall decrease in bleeding and spotting days over time; however, estimates derived from a variety of existing clinical data are currently unavailable. Objective The objective of the study was to systematically calculate the mean days of bleeding-only, spotting-only, and bleeding and/or spotting experienced by a population of reproductive-aged Levonorgestrel Intrauterine System users with normal regular menses prior to insertion during the first year of use. Data Sources We identified clinical trials, including randomized controlled trials and randomized comparative trials, as well as cohort studies published in English between January 1970 and November 2018 through searching 12 biomedical and scientific literature databases including MEDLINE and ClinicalTrials.gov . Study Eligibility Criteria We considered studies that reported data on Levonorgestrel Intrauterine System devices releasing 20 μg of levonorgestrel per day, collected daily menstrual bleeding data for at least 90 consecutive days, defined bleeding and spotting per World Health Organization standards and evaluated participants with normal regular menses prior to insertion. Study Appraisal and Synthesis Methods We assessed study quality using established guidelines. Two reviewers independently conducted all review stages and rated the quality of evidence for each article; any disagreements were resolved by a third. Where possible, we pooled data using a random-effects model. Results Among 3403 potentially relevant studies, we included 7 in our meta-analysis. We calculated the mean days of bleeding-only, spotting-only, and bleeding and/or spotting for the first four 90 day intervals after Levonorgestrel Intrauterine System insertion. Combined menstrual bleeding and/or spotting days gradually decreased throughout the first year, from 35.6 days (95% confidence interval, 32.2–39.1) during the first 90 day interval to 19.1 (95% confidence interval, 16.6–21.5), 14.2 (95% confidence interval, 11.7–16.8), and 11.7 days (95% confidence interval, 9.7–13.7) in the second, third, and fourth intervals. Measures for bleeding-only and spotting-only days similarly decreased throughout the first year, with the greatest decreases occurring between the first and second intervals. Conclusion Our study provides 90 day reference period measures that characterize menstrual patterns for Levonorgestrel Intrauterine System users with normal regular menses prior to insertion during the first year of use. Our findings provide broader generalizability and more detail than patterns described in the prescribing information. These findings quantify an overall decrease in menstrual bleeding days with longer duration of use, with the greatest decrease occurring between months 3 and 6. Accurately establishing expectations with the Levonorgestrel Intrauterine System may improve informed selection and decrease discontinuation.

Background Premenstrual syndrome is characterized by the cyclic occurrence of physical, behavioral and psychological symptoms during the luteal phase of the menstrual cycle disappearing within a few days of the onset of menstruation. Generally symptoms are mild, but 5–8% of women suffer from severe PMS. Apart from conventional drugs, like serotonin reuptake inhibitors and oral contraceptives, complementary and alternative medicines such as Vitex agnus castus are used by many women experiencing PMS. Objective Our objective was to determine the efficacy, tolerability, and acceptability of Vitex agnus castus preparations for treatment of premenstrual syndrome. Study Design All journals in the Ovid software from inception through January 2016 were searched, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and PsycINFO. Gray literature was searched by Google Scholar and manufacturers of Vitex agnus castus preparations were contacted for information about unpublished trials. We included randomized controlled trials with Vitex agnus castus in women with premenstrual syndrome and/or premenstrual dysphoric disorder with a minimal duration of 2 menstrual cycles. The eligibility of the manuscripts was assessed by 2 reviewers independently. The data abstracted included characteristics of the study design, characteristics of the patient population, intervention details, type of comparator, method of diagnosis, and outcome measures. We adhered to the PRISMA guidelines. Results We found 17 randomized controlled trials of Vitex agnus castus in the treatment of premenstrual syndrome. Fourteen of these could be included in the quantitative analysis. Thirteen of 14 studies with placebo, dietary supplements, or herbal preparations as controls reported positive effects of Vitex agnus castus on total premenstrual syndrome symptoms. Unfortunately most of the trials are associated with a high risk of bias. The pooled effect of Vitex agnus castus in placebo-controlled trials was large (Hedges g, –1.21; 95% confidence interval, –1.53 to –0.88), but heterogeneity was extremely high (I 2 , 91%). We were unable to single out factors that could explain this heterogeneity satisfactorily. The funnel plot and Egger tests suggest the presence of publication bias. Conclusion Although meta-analysis shows a large pooled effect of Vitex agnus castus in placebo-controlled trials, the high risk of bias, high heterogeneity, and risk of publication bias of the included studies preclude a definitive conclusion. The pooled treatment effects should be viewed as merely explorative and, at best, overestimating the real treatment effect of Vitex agnus castus for premenstrual syndrome symptoms. There is a clear need for high-quality trials of appropriate size examining the effect of standardized extracts of Vitex agnus castus in comparison to placebo, selective serotonin reuptake inhibitors, and oral contraceptives to establish relative efficacy.

The optimal interpregnancy interval after a single pregnancy loss is controversial. It is common obstetrical practice to recommend that women who have had a miscarriage in the first trimester of pregnancy should wait for 1 or more menstrual cycles before attempting to conceive again.This study aimed to assess whether conception before the first menstrual period after a spontaneous pregnancy loss is associated with a risk of repeat miscarriage or adverse perinatal outcomes.This retrospective cohort study included 107 women who had a spontaneous miscarriage in the first trimester of pregnancy followed by a subsequent pregnancy with an interpregnancy interval of12 weeks. All miscarriages had ended in either spontaneous expulsion of the products of conception or medical or surgical evacuation of the uterus. The perinatal outcome measures of 57 women who conceived after the first menstrual period following a spontaneous miscarriage were compared with perinatal outcome measures of 50 women who conceived before the first menstrual period following a spontaneous miscarriage. The primary outcome was rate of pregnancy loss, and the secondary outcomes were gestational age at delivery and birthweight.The rate of recurrent miscarriage was 10.4% for women who conceived before the first menstrual period following a spontaneous miscarriage and 15.8% for those who conceived after (P=.604). There were no differences in the gestational age at delivery (38.9 vs 38.7 weeks; P=.66) or the birthweight (3347±173 vs 3412±156 g; P=.5) between the 2 groups. Other outcomes, such as mode of delivery and 5-minute Apgar score, were also similar for both groups. A multiple logistic regression analysis confirmed that conception before the first menstrual period following a spontaneous miscarriage was not associated with a higher incidence of subsequent miscarriage (odds ratio, 1.74; P=.46) or any other untoward outcome.Conception shortly after a spontaneous miscarriage without waiting for at least the first postmiscarriage menstrual period is not associated with adverse maternal or neonatal outcomes compared with those of women with similar interpregnancy intervals who conceived after their next menstrual period.

Chronic pelvic pain is common among women of reproductive age and is associated with significant morbidity and comorbidities. In this Viewpoint, we explore the evolutionary cause of pelvic pain and summarize evidence that supports a menstruation-related evolutionary cause of chronic visceral pelvic pain: (1) lifetime menstruation has increased; (2) severe dysmenorrhea is common in the chronic pelvic pain population, particularly among those with pain sensitization; and (3) a potential biological mechanism can be identified. Thus, chronic pelvic pain may arise from the mismatch between the slow pace of biological evolution in our bodies and the relatively rapid pace of cultural changes that have resulted in increased menstrual frequency due to earlier menarche, later mortality, and lower fecundity. One possible mechanism that explains the development of persistent pain from repeated episodes of intermittent pain is hyperalgesic priming, a physiological process defined as a long-lasting latent hyperresponsiveness of nociceptors to inflammatory mediators after an inflammatory or neuropathic insult. The repetitive severely painful menstrual episodes may play such a role. From an evolutionary perspective the relatively rapid increase in lifetime menstruation experience in contemporary society may contribute to a mismatch between lifetime menstruation and the physiological pain processes, leading to a maladaptive state of chronic visceral pelvic pain. Our current physiology does not conform to current human needs.

Background Heavy menstrual bleeding is a leading cause of copper intrauterine device discontinuation. Thus, girls and women with heavy baseline menstrual bleeding may be at increased risk for early copper intrauterine device discontinuation. Objective Our objective was to assess if there was an association between baseline menstrual bleeding pattern prior to intrauterine device insertion and discontinuation rate at 12 months among study participants who chose copper intrauterine device at baseline. Study Design We performed a secondary analysis of the Contraceptive CHOICE Project, a prospective observational cohort study of 9256 girls and women offered no-cost contraception for 2–3 years. Included in our study were participants who chose copper intrauterine device for contraception and for whom method continuation data at 12 months were available. Prior to contraception initiation, participants were asked to qualify their menstrual bleeding over the past year as: light, moderate, moderately heavy, or heavy. Light bleeding corresponded to using ≤10 pads/tampons per period. Moderate, moderately heavy, and heavy bleeding corresponded to 11–20 pads/tampons, 21–30 pads/tampons, and >30 pads/tampons per period, respectively. Subjects were then categorized into either a “heavy” baseline group (those reporting moderately heavy or heavy bleeding at baseline), or a “not heavy” group (those reporting light or moderate bleeding). The 12-month continuation rate for each group was then calculated using Kaplan-Meier survival function, and hazard ratio for risk of discontinuation was evaluated using a Cox proportional hazard model to determine if moderately heavy or heavy bleeding at baseline was associated with early discontinuation. Results Of the 918 girls and women meeting the inclusion criteria for this analysis, 165 were in the heavy baseline bleeding group, while 753 were in the not heavy bleeding group. The 12-month continuation rates for groups were similar: 80.2% (heavy) and 85.0% (not heavy; P = .24). Patients reporting either moderately heavy or heavy baseline bleeding were not at increased risk for early discontinuation of copper intrauterine device (hazard ratio, 1.21; 95% confidence interval, 0.88–1.66). Our sample size provided >90% power to detect a clinically important difference of 15% (assuming 20% discontinuation rate in not heavy bleeding group and a 35% discontinuation rate in the heavy bleeding group). Conclusion We did not find that girls and women who reported baseline moderately heavy or heavy menstrual bleeding were at increased risk for early discontinuation. Thus, we do not believe that girls and women with heavy menstrual bleeding should be discouraged from using this safe and highly effective form of contraception.

The lack of noninvasive methods to study dysmenorrhea has resulted in poor understanding of the mechanisms underlying pain, insufficient diagnostic tests, and limited treatment options. To address this knowledge gap, we have developed a magnetic resonance imaging-based strategy for continuously monitoring the uterus in relationship to participants' spontaneous pain perception.The study objective was to evaluate whether magnetic resonance imaging can detect real-time changes in myometrial activity during cramping episodes in women with dysmenorrhea, with a handheld squeeze bulb for pain reporting.Sixteen women with dysmenorrhea and 10 healthy control women both on and off their menses were evaluated with magnetic resonance imaging while not taking analgesic medication. Continuous magnetic resonance imaging was acquired using half-Fourier acquisition single-shot turbo spin echo sequence along with simultaneous reporting of pain severity with a squeeze bulb. Pearson's coefficient was used to compare results between reviewers. Proportional differences between women with dysmenorrhea and controls on/off menses were evaluated with a Fisher exact test. The temporal relationships between signal changes were evaluated with Monte Carlo simulations.Spontaneous progressive decreases in myometrial signal intensity were more frequently observed in women on their menses than in the absence of pain in the same women off their menses or participants without dysmenorrhea (P.01). Women without reductions in myometrial signal intensity on their menses either had a history of endometriosis or were not in pain. Observations of myometrial events were consistently reported between 2 raters blinded to menstrual pain or day status (r = 0.97, P.001). Episodes of cramping occurred either immediately before or 32-70 seconds after myometrial signal change onset (P.05).Transient decreases in myometrial uterine T2-weighted signal intensity can be reliably measured in women with menstrual pain. The directionality of signal change and temporal relationship to pain onset suggest that cramping pain may be caused by a combination of uterine pressure and hemodynamic dysfunction.

Reproductive tract bleeding in women is a naturally occurring event during menstruation and childbirth. In women with menorrhagia, however, congenital bleeding disorders historically have been underdiagnosed. This consensus is intended to allow physicians to better recognize bleeding disorders as a cause of menorrhagia and consequently offer effective disease-specific therapies. © 2009 Mosby, Inc. All rights reserved.

The purpose of this study was to examine the influence of menstrual cycle and oral contraceptive use on serum levels of lipid-soluble antioxidants.In this cross-section study, nonfasting blood samples were collected twice from 10 healthy premenopausal women during the follicular phase (between days 8 and 11) and the luteal phase (between days 18 and 22) of their same menstrual cycle. In addition, blood samples from 15 premenopausal women who used oral contraceptive for at least 6 months and 40 women who did not use oral contraceptive were collected randomly at any day of the menstrual cycle. Serum levels of coenzyme Q10, alpha-tocopherol, gamma-tocopherol, beta-carotene, alpha-carotene, and lycopene were determined using high pressure liquid chromatography.Serum coenzyme Q10 and alpha-tocopherol levels were significantly lower during the follicular phase compared with the luteal phase of the same menstrual cycle (P.05). Oral contraceptive use also significantly decreased coenzyme Q10 and alpha-tocopherol (P.001). Other antioxidant levels were comparable.Alterations in coenzyme Q10 and alpha-tocopherol levels during the menstrual cycle and in oral contraceptive users should be taken into consideration, concerning the future antioxidant research in premenopausal women. Further studies are needed to investigate the potential role of endogenous and exogenous ovarian hormones on oxidative stress in women.

Objective We evaluated the tolerability of emergency contraception in adolescents. Study design In this descriptive study, 1 0.75 mg levonorgestrel tablet was administered to 52 females aged 13-16 with instructions to take the second tablet 12 hours later (unprotected intercourse was not an entry requirement). Participants kept diaries of side effects and menstrual patterns. We assessed correct use, side effects caused by treatment, and impact on menstrual cycle. Results Virtually all participants used the drug correctly, with no serious adverse events. Minor expected side effects occurred, including nausea, fatigue, and vomiting. There was no difference in reporting of side effects by age. Adolescents' mean duration of menses was comparable pre- and post-treatment (5.3 vs 5.0 days; P = .146), and onset of menses was within the expected range. Ninety percent of participants reported they would recommend emergency contraception to a friend or relative if needed. Conclusion Adolescents tolerated the medication well, experiencing transient side effects.

Objective Menorrhagia is defined in terms of statistical“abnormality”as blood loss of >80 mL. We examined the usefulness of this definition in women who were referred to gynecology clinics with heavy periods. Study design A questionnaire survey of 952 menstrual complaint referrals at 3 hospital gynaecology clinics in Glasgow and Edinburgh included 226 women with heavy periods who had also consented to the measurement of their blood loss. Results Women reported a range of problems with their periods, but absolute volume (31.2%) was less prevalent than period pain (37.5%), mood change (35.7%), and change in the amount (volume) of the period (33.8%). Although there were associations with volume, these associations were due to the heaviest and lightest of the loss groups, whereas the 2 groups with loss either side of 80 mL were virtually indistinguishable. Conclusion The 80-mL criterion for menorrhagia is of limited clinical usefulness because it is prognostic neither for problems nor iron status and apparently does not guide management.

Objective The purpose of this study was to investigate the validity of home pregnancy tests (HPTs) around the time of the missed menses. Study design Levels of human chorionic gonadotropin (hCG) were determined in urine around the time of the missed menses, and 5th and 95th centiles were calculated. In a blind study evaluating 18 brands of HPTs, each was tested six times with five concentrations of hCG, 0 to 100 mIU/mL. Sensitivity was defined as the concentration at which six of six brands gave positive results, at the suggested reading time or at an extended time. Results It was estimated that a sensitivity of 12.5 mIU/mL was needed to detect 95% of pregnancies at the time of missing menses. Only 1 of 18 HPTs had this sensitivity. If faintly discernible results considered, 2 of 18 brands gave false-positive or invalid results. Clear positive results were given by only 44% of the brands at 100 mIU/mL hCG. If one accepted faintly discernible and extended reading times, all brands responded at 100 mIU/mL. A test with 100 mIU/mL sensitivity would detect approximately 16% of pregnancies at the time of missed menses. Conclusion The utility of HPTs is questioned. Clinicians need to be aware of the limitations of current HPT brands.

The purpose of this study was to assess changes in menstrual pattern, quality of life, and patient satisfaction after thermal balloon ablation for abnormal uterine bleeding.One hundred forty-one women who underwent thermal balloon ablation in our institution initially had their charts reviewed for demographics, procedure data, clinical history, and follow-up. Thereafter, a telephone interview was conducted to assess postprocedural menstrual pattern, quality of life, and patient satisfaction. Data were compared with the use of appropriate tests for categoric or continuous variables and logistic regression.The median follow-up time was 18 months, and a telephone interview was obtained for 119 of 141 patients. A reduction in days per cycle (9.6 vs 3.1 days, P.0001) and in pads per day (12.8 vs 2.5 pads/d, P.0001) and an improvement in self-reported quality of life scores (2.8 vs 9.0, P.0001) were observed after thermal balloon ablation. Hysterectomy was required in 21 of 141 patients (15%). Assessment of the level of satisfaction showed that 96% of patients were satisfied or very satisfied with the procedure. No major complications or deaths were related to thermal balloon ablation.Thermal balloon ablation is a safe and efficient method to treat abnormal uterine bleeding. It reduces the menstrual flow, improves the quality of life, and remarkably fulfills expectations in selected patients.

Oral contraceptives are one of the most highly effective forms of contraception and provide many short- and long-term noncontraceptive health benefits. They control menstrual cycle irregularities, such as breakthrough bleeding and amenorrhea, and are effective in treating dysfunctional uterine bleeding. In addition, for decades after oral contraceptive use is discontinued they are associated with substantial decreases in the risk of ovarian cancer (up to 80%) and of endometrial cancer (40%-50%), and nearly eliminate benign functional ovarian cysts. Long-term oral contraceptive use confers protection against benign breast disease and colorectal cancer, may help prevent rheumatoid arthritis, decreases ectopic pregnancy and hospitalizations for pelvic inflammatory disease, and helps preserve bone mineral density to reduce risk of fractures. Large bodies of evidence from extensive research have clarified the perceived association of oral contraceptive use with cardiovascular disease and with breast cancer. Findings indicate that there is no increased risk of myocardial infarction or stroke associated with oral contraceptive use in healthy, nonsmoking, normotensive women. Although there is a 3- to 4-fold increased risk of venous thromboembolism with current oral contraceptive use, the absolute risk is very small and is half that associated with pregnancy. Women of all reproductive ages, including perimenopausal women, can realize many health benefits through oral contraceptive use, including improved health status later in life.

We studied bleeding patterns in postmenopausal women who were using 2 types of continuous combination regimens.A prospective, double-blind, randomized study of 208 postmenopausal women treated with conjugated estrogen, 0.625 mg, and medroxyprogesterone acetate, 5 mg, or with 17beta-estradiol, 2 mg, and norethindrone acetate, 1 mg.The mean number of bleeding days decreased during the first 4 months of treatment (P.002) but not thereafter. The number of bleeding days was fewer (P.002) and the time until amenorrhea was shorter (P.02) in patients receiving conjugated estrogen and medroxyprogesterone acetate than in patients receiving 17beta-estradiol and norethindrone acetate. The odds ratio for progression to amenorrhea with the use of conjugated estrogen and medroxyprogesterone acetate was 1.58, in comparison with the use of 17beta-estradiol and norethindrone acetate. A thick endometrium at the start of treatment resulted in more bleeding days than were found for a thin endometrium (P.03). Body mass index, age, and blood pressure had no predictive value for bleeding problems.Treatment with continuous combined conjugated estrogen and medroxyprogesterone acetate resulted in fewer bleeding problems than did treatment with 17beta-estradiol and norethindrone acetate. Endometrial thickness may help to predict the chance of achieving amenorrhea during early hormone replacement therapy.

Objectives: Our aim was to report a new approach of endoscopic management (endoloop and encircling suture methods) for interstitial or cornual pregnancy and to determine the safety and effectiveness of these procedures and their effects on subsequent pregnancies. Study Design: This is an uncontrolled retrospective review of 24 patients treated for interstitial pregnancies through endoscopic operations with 14 to 72 months of follow-up at a large urban medical center. Blood loss, operation time, changes of serum human chorionic gonadotropin levels, the resumption of menstruation, and subsequent pregnancy after operation were analyzed. Results: Among 24 interstitial pregnancies, 3 had ruptured at the time of operation and 21 had not ruptured. Treatment consisted of either the vasopressin and electric cauterization method, the endoloop before evacuation of the conceptus method, or the encircling suture before evacuation of the conceptus method. The blood loss and operation time (mean ± SD) for unruptured cases were 133 ± 134 mL and 51.6 ± 7.6 minutes in the vasopressin and electric cauterization group (n = 3), 32 ± 22 mL and 28.5 ± 6.4 minutes in the endoloop group (n = 15), and 40 ± 17 mL and 35.0 ± 5.0 minutes in the encircling suture group (n = 3). In 3 patients with ruptured pregnancy treated with the endoloop method, the blood loss and operation time (mean ± SD) were 1100 ± 854 mL and 82.5 ± 51.6 minutes. Any of these operative methods resulted in rapid decline of serum human chorionic gonadotropin levels within 1 week with the exception of 1 case, in which the endoloop method was used; this patient needed additional treatment with methotrexate. Seventeen patients desired pregnancy in the future, and 15 eventually became pregnant. One of these 15 pregnancies ended in an ectopic pregnancy on the opposite side 6 months after the interstitial pregnancy. Three ended in a spontaneous abortion, and 11 were delivered by elective cesarean section at term before labor started. Operative records of cesarean section in 8 patients delivered at our institution showed little or no adhesions or defect in the cornual area of the previous operation. Conclusion: The endoloop method and the encircling suture method are simple, safe, effective, and nearly bloodless. There were no uterine ruptures in the pregnancies subsequent to these methods of endoscopic management. (Am J Obstet Gynecol 2000;182:114-21.)

Objectives: This study was undertaken to evaluate the relationship between vaginal pH and factors related to cervical cancer. Study Design: In a population-based sample of 9161 women from Guanacaste Province in Costa Rica women were categorized into 2 groups, those with vaginal pH in the reference range (4.0-4.5) and those with elevated vaginal pH (5.0-5.5). Odds ratios were used to estimate the relationship between elevated pH and its potential determinants. Results: Aging was strongly associated with increasing vaginal pH, starting at around 45 years of age and continuing into old age. Menopause was responsible for an additional 1.7-fold increase in the odds of having an elevated pH (odds ratio 1.7, 95% confidence interval 1.4-2.0). Human papillomavirus infection and cervical intraepithelial neoplasia were not associated with changes in pH. Conclusions: Our data indicate that vaginal pH is strongly related to age and to menopausal status and thus could be a marker of age-related hormonal changes. Elevated pH does not appear to be associated with risk of high-grade intraepithelial neoplasia among women infected with human papillomavirus. (Am J Obstet Gynecol 1999;180:1060-6.)

Prepubertal vaginal bleeding is considered as isolated menarche when, in the absence of detectable abnormality, it is not accompanied by any evidence of sexual development. The etiology remains unclear and various hypotheses have been put forward. This is the first time that a series of ultrasound patients with prepubertal menarche whose investigation has included imaging with ultrasound has been described. This paper illustrates isolated prepubertal menarche without the presence of an endometrial echo.

Advances in research relating to menstruation and associated disorders (eg, endometriosis and premenstrual syndrome) have been hindered by the lack of an appropriate animal model. Menstruation, the cyclical shedding of the decidualized endometrium in the absence of pregnancy, is believed to be limited to 78 higher-order primates (human beings and Old World monkeys), 4 species of bat, and the elephant shrew. This represents only 1.5% of the known 5502 mammalian species and0.09% of these are nonprimates. Thus, many aspects of menstruation remain poorly understood, limiting the development of effective treatments for women with menstrual disorders. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents.Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus).Virgin female spiny mice (n = 14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and enzyme-linked immunosorbent assay of progesterone (n = 4-5/stage of the menstrual cycle). Normally distributed data are reported as the mean ± SE and significant differences calculated using a 1-way analysis of variance. Nonnormal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test.Mean menstrual cycle length was 8.7 ± 0.4 days with red blood cells observed in the lavages over 3.0 ± 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase at 322.6 μm (254.8, 512.2), when plasma progesterone peaked at 102.1 ng/mL (70.1, 198.6) and the optical density for prolactin immunoreactivity was strongest (0.071 ± 0.01 arbitrary units).The spiny mouse undergoes spontaneous decidualization, demonstrating for the first time menstruation in a rodent. The spiny mouse provides a readily accessible nonprimate model to study the mechanisms of menstrual shedding and repair, and may therefore be useful in furthering studies of human menstrual and pregnancy-associated disorders.

OBJECTIVE: The Sampson hypothesis of retrograde menstruation as a cause of endometriosis was tested by determining the effect of intrapelvic injection of menstrual versus luteal endometrium on the incidence, peritoneal involvement, and stage of endometriosis. STUDY DESIGN: Seventeen baboons were injected retroperitoneally with luteal ( n = 6) or menstrual ( n = 7) endometrium and intraperitoneally with menstrual endometrium ( n = 4). Laparoscopies were performed after 2 months in all animals and after 5 and 12 months in six and five primates injected with luteal and menstrual endometrium, respectively. RESULTS: The peritoneal endometriosis surface area, number of implants, and incidence of typical and red subtle lesions were significantly higher after retroperitoneal injection of menstrual than of luteal endometrium. By use of menstrual endometrium intraperitoneal seeding was more successful in causing endometriosis than was retroperitoneal injection. No significant changes in number or surface area of endometriotic lesions induced with retroperitoneal injection of luteal endometrium after 5 months were observed in the six baboons. At repeat laparoscopy 12 months after intrapelvic injection of menstrual endometrium progression was recorded in three of four regularly cycling animals, whereas regression was evident in one baboon that had become amenorrheic after induction. CONCLUSION: Intrapelvic injection of menstrual endometrium can cause peritoneal endometriosis and offers experimental evidence supporting the Sampson hypothesis

OBJECTIVE: We compared continuation rates, effectiveness, satisfaction with method, side effects, and condom practices among adolescents using levonorgestrel implants (Norplant, Wyeth-Ayerst Laboratories, Philadelphia) as compared with oral contraceptives. STUDY DESIGN: We conducted a case-control study comparing 94 adolescents ≤ 18 years odl who received Norplant between March 1, 1992, and Nov. 1, 1993 (cases), with 94 age-matched controls who selected oral contraceptives during this same time period. By use of a structured questionnaire, information was obtained on pregnancy status, duration of use, patient satisfaction, side effects, and condom practices 6 months after initiation. Objective measures included weight on Norplant and oral contraceptive users and hematocrit on implant patients. RESULTS: Forty (43%) oral contraceptive patients compared with no Norplant patients discontinued their selected method before the 6-month interview ( p = 0.00). Six patients prescribed oral contraceptives became pregnant. Ninety-three percent of Norplant users expressed overall satisfaction despite experiencing menstrual irregulatiry and cramping, amenorrhea, nervousness, abnormal hair growth or loss, rashes, and an increase in appetite more often than oral contraceptives users. Although Norplant patients also reported an increase in the duration of menstrual flow and number of days of spotting more often than oral contraceptive users, evaluation of hematocrits in these patients demonstrated a significant increase over the 6-month period ( p = 0.00). Assessment of condom practices since initiation demonstrated that Norplant patients used condoms less often than oral contraceptive users ( p - 0.00). CONCLUSION: Use of levonorgestrel implants may cause more side effects than oral contraceptives in the early months after initiation but provide superior protection against unintended pregnancy. We concluded that Norplant is a reasonable alternative for adolescents, especially when compliance is an issue.

Persistent bleeding is a common reason for the discontinuation of contraception. Standard terminology for describing bleeding patterns by reference period is presented. Observed bleeding patterns with oral contraceptives, depot medroxyprogesterone acetate, the levonorgestrel subdermal implant, and intrauterine devices are described. Bleeding days are least with oral contraceptives that are highest in progestin and estrogen potency and dose, but the ratio of the two steroids is also important. Published studies suggest that oral contraceptives containing new nonandrogenic progestins have bleeding patterns as acceptable as older low estrogen formulations. Approaches to the evaluation and treatment of intermenstrual bleeding with contraceptive methods are reviewed. Patient education on expected bleeding patterns is essential to compliance and continuation.Many women discontinue hormonal contraceptives because of persistent bleeding. Discontinuation can result in unwanted pregnancy. Hormonal contraceptives may have 2 effects on the menstrual cycle: continued cyclic bleeding or partial or complete suppression of the normal cycle. Oral contraceptives (OCs) suppress the normal ovarian cycle with an artificial cycle caused by withdrawal of the hormones on day 21. Progestin-only OCs, subdermal implants, injectable steroids, and the levonorgestrel-releasing IUD cause partial or complete suppression of the normal cycle. OCs with the highest progestin and estrogen potency and dose are associated with the least number of bleeding days. The ratio of the 2 steroids may affect bleeding. For example, an increase in either steroid appears to decrease breakthrough bleeding (BTB). In some women, BTB or spotting is associated with OC use. Clinical trials of OCs do not use standard terminology and definitions, making it difficult to analyze bleeding patterns. OCs with the new nonandrogenic progestins and low-estrogen doses tend to effect acceptable bleeding patterns similar to those of the older low-dose estrogen OCs. Among Norplant users experiencing persistent bleeding, levonorgestrel (0.03 mg 2 times/day for 20 days), ethinyl estradiol (0.05 mg/day for 20 days), and ibuprofen (800 mg 3 times/day for 5 days) reduce bleeding days and episodes of treatment. Some possible regimens to treat persistent bleeding in OC users include 7 day courses of estrogen (0.02 mg ethinyl estradiol or 2.5 mg conjugated equine estrogens). When BTB occurs in an OC user who has previously had normal menstrual cycles, providers should consider causes other than OCs, such as trauma-vaginal laceration, cervical lesion, endometrial lesion, fallopian tube cancer, and pregnancy. They should deliver good patient education on bleeding patterns to achieve good compliance and continuation.

Currently, there are >2 million survivors of breast cancer in the United States. Two years after cancer treatment, patients may transition to primary care providers and/or gynecologists. Many of these survivors may have difficulties with menopausal symptoms. If they do not know already, some of these women may want or need risk assessment for hereditary- or treatment-induced second cancers. At least 20% will also have significant psychologic, sexual, and/or relationship difficulties that require attention. All of the women will need assistance to learn and follow recommendations for surveillance, detecting recurrence, and promoting wellness. Thus, gynecologists play a critical role in helping these patients in their health care transitions. To assist the gynecologists, we have reviewed the evaluation and management of common sequelae of breast cancer diagnoses and treatments.

Our aim was to characterize the influence of breast-feeding on the postpartum return of ovarian activity for the purpose of assessing the relevance of the lactational amenorrhea method of contraception for women in the United States.Twenty-two non-breast-feeding and 60 breast-feeding women from Baltimore collected daily urine specimens that were assayed to determine ovulation and luteal phase adequacy. Vaginal bleeding was ascertained weekly, and breast-feeding women recorded infant feeding daily. Proportion-hazards models were used to relate measures of breast-feeding to the occurrence of ovulation.Two thirds of women ovulated before their first vaginal bleeding, but 47% of those cycles had decreased luteal-phase pregnanediol excretion. Breast-feeding frequency and suckling duration were significant predictors of the risk of ovulation (p0.001). Supplementation with bottle feeding was associated with a reduction in breast-feeding.A high degree of protection from pregnancy can be achieved using breast-feeding frequency and suckling duration, even with supplemented breast-feeding.Between 1983 and 1987 in Baltimore, Maryland, researchers followed 60 breast-feeding mothers (55% single and 82% black) and 22 non breast feeding mothers (3% single and 93% white) for 72 weeks to better understand resumption of postpartum ovarian activity and the impact breast feeding has on resumption of ovarian activity. Laboratory personnel conducted daily urinary assays to detect ovulation and to evaluate the luteal phase. Ovulatory first vaginal bleeding episodes increased with the time (45% in the first 12 weeks to 100% after 49 weeks). 69% of breast-feeding mothers experienced an ovulatory first bleeding episode, but 47% of these cycles had reduced excretion of pregnanediol during the luteal phase, indicating a reduced likelihood of conception before first bleedings. The women's descriptions of perceived characteristics of their bleeding episodes were linked to ovulatory or anovulatory status. Specifically, women who reported regular or heavy bleeding were more likely to have had a preceding ovulation than those who reported spotting or light bleeding (84% vs. 35%; odds ration = 9.8; p .001). Resumption of ovulation was delayed in breast-feeding mothers. All non breast-feeding mothers menstruated within the first 12 weeks postpartum compared with just 20% of breast- feeding mothers. First ovulation occurred on average 45 days after delivery among non breast-feeding mothers and 189 days among breast- feeding mothers. The multivariate analysis revealed that breast-feeding episode contributed greatly and independently to the delay in ovulation (relative risk = .66 and .91, respectively; p .001). The protected effected of breast feeding remained even when mothers supplemented with bottle feeds 92% pregnancy rate over 6 months for both exclusive and partial breast feeders). These results indicated that breast feeding of increased frequency and suckling duration provides considerable protection from pregnancy, even when mothers use supplements.

Objective: We tested a new hormone replacement formulation based on the hypothesis that interrupted administration of progestin in the presence of continuous estrogen would result in receptor up-regulation and resensitization of target tissues to both estrogen and progestin. As a result, symptom control might be possible with lower doses of steroids and in the absence of withdrawal bleeding. Study Design: Forty postmenopausal women were entered in a 6-month pilot study, including an 18-month extension. They received piperazine estrone sulfate 0.75 mg daily. Norethindrone 0.35 mg daily was added in 3-day phases, alternating with progestin-free phases of 3 days. There was no steroid-free withdrawal period. We examined symptom control, bleeding patterns, endometrial protection, and lipid profiles in the women over the 24 months of the study. Results: Hot flushes were completely eliminated in 76% of women, and 80% had no bleeding by 6 months. There were three dropouts. Thirty-three women elected to continue after the first 6 months and completed 24 months on therapy for a compliance rate of 82.5%. No endometrial hyperplasia was seen on serial biopsies, and no changes occurred in lipids except for a small but statistically significant decrease in high-density lipoproteins and triglycerides at 24 months. Conclusion: Our preliminary results of low bleeding rates, good symptom control, and endometrial protection, suggest that hormone replacement with low-dose estrogen and interrupted progestin is effective and may lead to improved compliance in menopausal women.

OBJECTIVE: The purpose of this study was to develop a gestational age table by means of crown-rump length measurements in the first trimester in pregnancies conceived through in vitro fertilization. STUDY DESIGN: Ninety-four infertile women with singleton intrauterine pregnancies resulting from in vitro fertilization underwent ultrasonographic examinations in the first trimester. The relationship between gestational age (calculated with the day of oocyte retrieval used as day 14) and the crown-rump length was explored with regression analysis. RESULTS: A quadratic model demonstrated the best fit to the data, indicating a curvilinear relationship between crown-rump length and gestational age. Estimates of gestational age with crown-rump length measurements between 40 and 60 mm were observed to be similar to published tables, but outside this range the tables either overestimate or underestimate the true gestational age. CONCLUSION: A more accurate equation for gestational age estimation with crown-rump length measurements in early pregnancy has been developed with in vitro fertilization pregnancy data.

The pre- and postovulatory phases of the menstrual cycle are as variable in length as the cycle as a whole in the macaque (Hartman). Such variability can readily be explained in a cycle controlled by a balanced system of endocrine forces. Ovulation is demonstrated on the 21st to the 23rd, 29th, 29th to the 30th, 30th, and 36th days after the onset of normal menstrual periods in a colony of healthy, mature macaques. There is evidence that such delayed ovulation occurs more frequently than these five crucial cases would indicate. Delayed ovulation in these cases was due to a postmenstrual period of ovarian inactivity.

Pregneninolone may be used for the treatment of oligomenorrhea and secondary amenorrhea in adolescent girls. It is beneficial for some selected patients, particularly those with severe nervousness or dysmenorrhea when advice and observation do not suffice. For the patient who obtains relief from the use of pregneninolone, its administration is believed to be preferable to parenteral endocrine therapy or to large dosage with sedatives or analgesics which may be harmful. This hormone is given to prevent the occurrence of symptoms rather than to relieve those present. The initiation of bleeding has a pyschological advantage. Forty-six girls were treated. Twenty-nine, or 87 per cent, of the thirty-three girls with cycles of three months or less were improved. Pregneninolone is not recommended for those with cycles of longer than six months or for primary amenorrhea, as results were poor in these groups. Although the effect of taking pregneninolone tablets is largely temporary, a follow-up record of thirty patients with improved menstrual cycles showed that twelve, or 40 per cent, continued to menstruate regularly and approximately on time during the six months following completion of treatment.

1. 1. The uterine fibroid is a benign neoplasm, and its mere presence should be no cause for surgery. 2. 2. Only incontrovertible reasons, such as hemorrhage, pain, pressure symptoms, signs of tumor degeneration, rapid growth, interference with the pregnant states, cosmetic, and marital purposes should indicate surgical intervention. 3. 3. Myomectomy, even multiple, whereby endocrine balance, menstruation, and reproductive possibility are preserved, should be preferable to hysterectomy. 4. 4. The preoperative, operative, and postoperative preparation, technique, and care, respectively, as herein outlined, have enabled us to perform successfully 900 consecutive myomectomies for the interstitial and submucous types of fibroids with complete control and/or prevention of infection. 5. 5. The objections by opponents of myomectomy such as hemorrhage, infection, adhesions, and tumor recurrence have been effectively overcome in our procedures. 6. 6. This paper is presented with the hope that the widespread use of myomectomy, as described, will merit its recognition as the procedure of choice in the surgical treatment of uterine fibroids.

F ROM observations beginning in 1942,l we can state that androgen will not cure “external” endometriosis, exerts relatively little regressive effect upon hard infiltrates or fused masses as compared to cystic endometriomas, and, apart from the menopausal period, has but temporary action. Also, it may induce arrhenomimetic symptoms, which are always objectionable, possibly serious and permanent,* but, except from heavy prolonged dosage, are not inevitable and may be mild. Notwithstanding the above, aside from relation to endometriosis, androgen has both negative and positive values. Unlike estrogen, it is neither experimentally3 nor clinically fibromatogenic or carcinomatogenic,3al 4 but rather antigenie in these respects, particularly versus inception of mammary cancer.5 It has positive value in spasmodic dysmenorrhea and mastalgia, less value in premenstrual tension6 and “functional uterine bleeding,‘” although not comparable to estrogen*’ 8 for the latter condition. Androgen also exhibits a “tonic” effect approaching euphoria notably at the menopause, when other favorable action may be prominent.a* lo In relation to endometriosis, androgen has also both negative and positive values. Unlike estrogen, it will not reactivate the disease after the menopause,llT I2 and, according to two of our cases, will not cause regression of cystic ovaries associated with peri-oophoritis and excessive bleeding. Although androgen has been used for acute pelvic inflammatory disease to suppress menstruation, we have not seen regression of inflammatory residues, and therefore suggest the last two negative observations as diagnostic possibilities. The positive values of androgen, particularly in rapid reduction of pain, tenderness, and swelling of grossly cystic ovarian endometriomas, will be described in 19 brief case reports under diagnostic, therapeutic, preoperative, and postoperative headings, not including a larger number of early nodular cul-de-sac endometriosis with minor symptoms. Contrary to original intention, only inconclusive haphazard endometrial biopsies and vaginal smears were obtained and no hormonal assays13v I4 so that nothing new can be presented as to etiology of the disease or biologic action of androgen. However, the rapidity of effect suggests a direct antagonism of androgen versus estrogen, in addition to known reduction of urinary gonado. tropic hormone excretion, as indicated in two previous reports.‘1 I5 We have had no experience with the sterol desoxycorticosterone acetate, and no conclusive effect with progestin, each of which should theoretically