Beyond Birth Control: The Neuroscience of Hormonal Contraceptives.

Hormonal contraceptives (HCs) are one of the most highly prescribed classes of drugs in the world used for both contraceptive and noncontraceptive purposes. Despite their prevalent use, the impact of HCs on the brain remains inadequately explored. This review synthesizes recent findings on the neuroscience of HCs, with a focus on human structural neuroimaging as well as translational, nonhuman animal studies investigating the cellular, molecular, and behavioral effects of HCs. Additionally, we consider data linking HCs to mood disorders and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress response as a potential mediator. The review also addresses the unique sensitivity of the adolescent brain to HCs, noting significant changes in brain structure and function when HCs are used during this developmental period. Finally, we discuss potential effects of HCs in combination with smoking-derived nicotine on outcomes of ischemic brain damage. Methodological challenges, such as the variability in HC formulations and user-specific factors, are acknowledged, emphasizing the need for precise and individualized research approaches. Overall, this review underscores the necessity for continued interdisciplinary research to elucidate the neurobiological mechanisms of HCs, aiming to optimize their use and improve women's health.

Influence of endogenous and exogenous hormones on the cardiovascular response to lower extremity exercise and group III/IV activation in young females.

Oral contraceptive (OC) use can increase resting blood pressure (BP) in females as well as contribute to greater activation of group III/IV afferents during upper body exercise. It is unknown, however, whether an exaggerated BP response occurs during lower limb exercise in OC users. We sought to elucidate the group III/IV afferent activity-mediated BP and heart rate responses while performing lower extremity tasks during early and late follicular phases in young, healthy females. Females not taking OCs (NOC: n = 8; age: 25 ± 4 yr) and those taking OCs (OC: n = 10; age: 23 ± 2 yr) completed a continuous knee extension/flexion passive stretch (mechanoreflex) and cycling exercise with subsystolic cuff occlusion (exercise pressor reflex), which was followed by a 2-min postexercise circulatory occlusion (PECO) (metaboreflex). Data collection occurred on two occasions: once during the early follicular phase (days 1-4) and once during the late follicular phase (days 10-14) of their menstrual cycle (NOC) or during the placebo and active pill phases (OC). Resting mean arterial BP and heart rate were not different between phases in NOC and OC participants (P > 0.05). Hemodynamic responses to metaboreflex, mechanoreflex, and collective exercise pressor reflex activation were not different between phases in both groups (P > 0.05). In conclusion, although OCs are known to increase BP at rest, our findings indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during large, lower limb muscle exercise with or without group III/IV afferent activation in young, healthy females.NEW & NOTEWORTHY Sex differences in the cardiovascular response to exercise have been demonstrated and may be dependent on sex hormone levels. Furthermore, oral contraceptives (OCs) have been shown to exaggerate the blood pressure response to upper extremity exercise. The results of this study indicate that neither endogenous nor exogenous (OC) sex hormones modulate BP during lower extremity dynamic exercise or with group III/IV afferent activation in young, healthy females.

Ovulatory cycle shifts in human motivational prioritisation of sex and food.

Previous research on the endogenous effects of ovarian hormones on motivational states in women has focused on sexual motivation. The Motivational Priority Shifts Hypothesis has a broader scope. It predicts a shift from somatic to reproductive motivation when fertile. In a highly powered preregistered online diary study across 40 days, we tested whether 390 women report such an ovulatory shift in sexual and eating motivation and behaviour. We compared 209 naturally cycling women to 181 women taking hormonal contraceptives (HC) to rule out non-ovulatory changes across the cycle as confounders. We found robust ovulatory decreases in food intake and increases in general sexual desire, in-pair sexual desire and initiation of dyadic sexual behaviour. Extra-pair sexual desire increased mid-cycle, but the effect did not differ significantly in HC women, questioning an ovulatory effect. Descriptively, solitary sexual desire and behaviour, dyadic sexual behaviour, appetite, and satiety showed expected mid-cycle changes that were diminished in HC women, but these failed to reach our strict preregistered significance level. Our results provide insight into current theoretical debates about ovulatory cycle shifts while calling for future research to determine motivational mechanisms behind ovulatory changes in food intake and considering romantic partners' motivational states to explain the occurrence of dyadic sexual behaviour.

Insights into the Behavior of Triple-Negative MDA-MB-231 Breast Carcinoma Cells Following the Treatment with 17ß-Ethinylestradiol and Levonorgestrel.

Oral contraceptives (OCs) are widely used due to their efficiency in preventing unplanned pregnancies and treating several human illnesses. Despite their medical value, the toxicity of OCs remains a public concern. Previous studies indicate the carcinogenic potential of synthetic sex hormones and their link to the development and progression of hormone-dependent malignancies such as breast cancer. However, little is known about their influence on the evolution of triple-negative breast carcinoma (TNBC), a malignancy defined by the absence of estrogen, progesterone, and HER2 receptors. This study reveals that the active ingredients of modern OCs, 17ß-Ethinylestradiol, Levonorgestrel, and their combination induce differential effects in MDA-MB-231 TNBC cells. The most relevant behavioral changes occurred after the 24 h treatment with 17ß-Ethinylestradiol, summarized as follows: (i) decreased cell viability (64.32% at 10 µM); (ii) cell roundness and loss of confluence; (iii) apoptotic aspect of cell nuclei (fragmentation, membrane blebbing); and (iv) inhibited cell migration, suggesting a potential anticancer effect. Conversely, Levonorgestrel was generally associated with a proliferative activity. The association of the two OCs exerted similar effects as 17ß-Ethinylestradiol but was less effective. Further studies are necessary to elucidate the hormones' cytotoxic mechanism of action on TNBC cells.

Venous thromboembolism in the hormonal milieu.

PURPOSE OF REVIEW: Hormonal therapy is administered for multiple indications including contraception, alleviation of menopausal symptoms, hypogonadism, and more recently, gender-affirming care. Data suggest varying degrees of increased risk for venous thromboembolism (VTE). RECENT FINDINGS: While oral progestin only methods do not appear to increase the risk of VTE, an association was seen with injection progestin contraception. Combined oral contraception with low-dose ethinyl estradiol and most types of progestin increased the risk of VTE compared with levonorgestrel-containing oral therapies. While transdermal hormonal contraception has been previously associated with increased VTE, a recently approved levonorgestrel and ethinyl estradiol transdermal patch reported low rates (<0.2%) in a large single-arm open-label study. Women receiving postmenopausal HRT experienced an increased risk of VTE in a dose-dependent manner when using oral hormonal therapy while nonoral methods, such as topical estrogen, did not appear to increase the risk of VTE. Some studies suggest no increased risk of VTE with testosterone therapy, however, a recent case-crossover study suggested higher VTE risk in men on testosterone, particularly men less than age 65 without hypogonadism. Route of administration had no effect on VTE rates. The estimated incidence rate of VTE risk in transgender women receiving estrogen therapy is 2.3 per 1000 person years, but may be imprecise due to heterogeneity in studies included in published meta-analyses. Surgical risk estimates are primarily indirect data drawn from cisgender patients receiving hormone therapy in the perioperative setting. SUMMARY: Hormonal therapy affects VTE risk to varying degrees dependent on specific type of hormone, formulation, and occasionally route of delivery.

Natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions.

High-grade serous carcinoma is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell-of-origin of high-grade serous carcinoma, acquiring TP53 mutation, evolving to tubal precursor lesions, including "p53 signature" and serous tubal intraepithelial carcinoma, and metastasizing to the ovary as clinically evident ovarian cancer. The etiological mechanisms associated with known epidemiological risk factors, i.e., ovulation and retrograde menstruation, have also been suggested. Mutagens and transforming growth factors, such as reactive oxygen species and insulin-like growth factor axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. In accordance with the proposed cleansing effect of progesterone from studies on oral contraceptive use or term pregnancy, a recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor. In this report, by analyzing different time effects of oral contraceptive use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and cleansing clearance concepts of ovulation and progesterone, as well as the fact of progressive loss of progesterone receptor during tubal transformation, we deduced the natural history of ovarian high-grade serous carcinoma. The natural history begins at the first ovulation and spans for more than 30 years, taking 10 years from the normal tubal epithelium to the "p53 signature" status, another 15 years to progesterone receptor negative serous tubal intraepithelial carcinoma, and a final 5+ years to high-grade serous carcinoma. The estimated natural history may help understand the pathogenesis of high-grade serous carcinoma and defines the window for early detection and chemoprevention.

No evidence that hormonal contraceptive use or circulating sex steroids predict complex emotion recognition.

Relatively little is known about the effects of endogenous and exogenous steroid hormones on ecologically relevant behavioral and cognitive phenotypes in women, such as emotion recognition, despite the widespread use of steroid hormone-altering hormonal contraceptives (HCs). Though some previous studies have examined the effect of HC use, estradiol, progesterone, and testosterone on emotion recognition in women, they have been limited by cross-sectional designs, small sample sizes (total n < 100), and compromised statistical power to detect significant effects. Using data from two test sessions in a large sample of naturally cycling women (NC; n = 192) and women on HCs (n = 203), we found no group differences in emotion recognition; further, the lack of group differences in emotion recognition was not modulated by item difficulty or emotional valence. Among NC women who provided saliva samples across two sessions that were assayed for estradiol and progesterone concentrations, we found no compelling evidence across models that between-subject differences and within-subject fluctuations in these ovarian hormones predicted emotion recognition accuracy, with the exception that between-subjects estradiol negatively predicted emotion recognition for emotions of neutral valence (p = .042). Among HC women who provided saliva samples across two sessions that were assayed for testosterone, we found no compelling evidence that between-subjects differences and within-subject fluctuations in testosterone predicted emotion recognition accuracy. Overall, our analyses provide little support for the idea that circulating endogenous or exogenous ovarian hormones influence emotion recognition in women.

Hormonal contraceptive use and subjective sleep reports in women: An online survey.

Female sexual hormones have known hypnogenic effects and the use of hormonal replacement therapy in postmenopausal women leads to improvement in sleep quality. However, the effects of hormonal contraceptives in women of reproductive age are still scarcely understood. This study sought to evaluate the impact of hormonal contraceptive use on subjective self-reports of sleep through a web-based cross-sectional survey. A total of 2,055 women between 18 and 40 years old participated by answering an online questionnaire evaluating hormonal contraceptive use, sleep-related characteristics and related features. Sleep assessment tools comprised the Epworth Sleepiness Scale (ESS) and the Insomnia Severity Index (ISI). Statistical comparisons were performed between hormonal contraceptive users and those who reported no current use. Analyses were repeated to compare users of combined contraceptives with users of progestagens only, as well as to compare users of different generations of contraceptives. Among the total sample, 1,286 participants met the inclusion criteria (918 of them were currently taking a hormonal contraceptive). Contraceptive users reported more frequent sleep complaints and had higher scores on ESS and ISI, which means increased excessive daytime sleepiness and more insomnia symptoms. Women using progestagen-only therapies reported lower total sleep duration compared with combined therapy. Users of third-generation contraceptives showed lower total sleep time and higher ISI score when compared with non-users. In conclusion, contraceptive users have more insomnia symptoms and increased excessive daytime sleepiness when compared with women who do not use any hormonal contraceptive method, and progestagen-only therapy was associated with lower sleep duration.

Variations in sleep associated with different types of hormonal contraceptives.

Progesterone and some of its metabolites are neuroactive steroids that affect sleep by increasing melatonin secretion and stimulating GABA-A receptors. The effect of progestogens in hormonal contraceptives on sleep has not been thoroughly investigated. This observational study assessed possible associations in sleep changes induced by estrogen-progestogens in contraceptives in 108 women between the ages of 20 and 50 years. We assessed mean nightly sleep time with a 31-day sleep diary, and subjective sleep quality with the five subjective subscores of the Pittsburgh Sleep Quality Index (PSQI). Included women were of childbearing age, healthy, sexually active and had been using a hormonal contraceptive method (pill, intrauterine system (IUS), subcutaneous implant, vaginal ring) for at least six months. Results were compared to a matched control group that did not use hormonal contraceptives. The longest mean nightly sleep time, compared to control (450 min), occurred in women who used progestogen-only oral contraception (510 min), followed by IUS delivery of levonorgestrel 13.5 mg (480 min) and oral ethinylestradiol 0.02/0.03 mg plus gestodene 0.075 mg (475 min). Global subjective sleep quality was influenced most by the administration of etonorgestrel 0.120 mg/ethinylestradiol 0.015 mg via the vaginal route. Our results show that low-doses of progestins affect various aspects of sleep, and that this is influenced by the route of administration.

The impact of oral hormonal contraception on metformin action on hypothalamic-pituitary-thyroid axis activity in women with diabetes and prediabetes: A pilot study.

WHAT IS KNOWN AND OBJECTIVE: The impact of metformin on thyrotropin levels is sex-dependent. No previous study has assessed whether sex steroids determine metformin action on thyrotrope and thyroid cell functioning. The aim of the present study was to compare the effect of this agent on hypothalamic-pituitary-thyroid axis activity and thyroid function tests between women receiving oral contraceptive pills and women not using any contraception. METHODS: The study population included 52 women with subclinical hypothyroidism and prediabetes or diabetes, 20 of whom had been using oral contraceptive pills for at least 12 months before the beginning of the study. Over the entire study period (4 months), all participants received oral metformin (1.7-3 g daily). Circulating levels of glucose, insulin, thyrotropin, free thyroid hormones, oestradiol, gonadotropins and prolactin were measured, while the structure parameters of thyroid homeostasis and the degree of insulin sensitivity were calculated at the beginning and at the end of the study. RESULTS AND DISCUSSION: The study groups differed in oestradiol, gonadotropins and prolactin levels and in structure parameter inference approach (SPINA)-GT. In both groups, metformin reduced glucose levels, homeostasis model assessment 1 of insulin resistance index (HOMA1-IR), thyrotropin levels and Jostel's thyrotropin index, as well as increased SPINA-GT. In women receiving oral contraceptive pills, the drug slightly decreased serum prolactin levels. The impact on metformin on HOMA1-IR, thyrotropin, prolactin, Jostel's thyrotropin index and SPINA-GT was more pronounced if women received oral contraception, as well as more pronounced in patients treated with higher doses of this agent. Treatment-induced changes in thyrotropin and Jostel's thyrotropin index correlated with their baseline values, baseline levels of oestradiol and gonadotropins, as well as with the degree of a reduction in HOMA1-IR. WHAT IS NEW AND CONCLUSION: This study is the first one to have shown that oral oestrogens potentiate the effect of metformin on hypothalamic-pituitary-thyroid axis activity.

Comparison of effect of preoperative dienogest and gonadotropin-releasing hormone agonist administration on laparoscopic cystectomy for ovarian endometriomas.

PURPOSE: To compare the effects of preoperative dienogest (DNG) and gonadotropin-releasing hormone (GnRH) agonist administration on the improvement of preoperative symptoms and surgical outcomes in patients who underwent laparoscopic cystectomy for ovarian endometriomas. METHODS: Seventy patients who were scheduled for laparoscopic surgery were enrolled in the study. They were divided into two groups: 35 patients who received DNG for 4 months preoperatively (group D) and 35 patients who received low-dose sustained-release goserelin acetate for 4 months preoperatively (group G). Preoperative outcomes, including pain score associated with endometriosis, using the numerical rating scale (NRS), adverse events of hormonal therapy and Kupperman index (KI) before and after treatment, surgical outcomes including total surgical duration and blood loss, and postoperative recurrence of endometrioma were compared between the two groups. RESULTS: Regarding preoperative symptoms, NRS and KI at 4 months after preoperative hormonal therapy were significantly lower in group D than in group G (NRS, 5.3 ± 5.5 vs. 2.7 ± 3.9; P = 0.01; KI, 16.0 ± 11.0 vs. 9.2 ± 7.6; P = 0.006). Regarding adverse events, the incidence of hot flashes was significantly lower in group D than in group G (P < 0.001). Meanwhile, the incidence of breast pain and metrorrhagia was significantly higher in group D than in group G (P = 0.04 and P < 0.001, respectively). The total surgical duration and blood loss were not significantly different between the groups. At 12 months after surgery, ovarian endometrioma did not recur in either group. CONCLUSION: Preoperative administration of DNG is more valuable for patients with endometriosis and scheduled for laparoscopic surgery to improve symptoms with good efficacy and tolerability than the administration of GnRH agonist.

Migraine: navigating the hormonal minefield.

Migraine affects 959 million people worldwide,1 with the highest prevalence being in women of childbearing age. The interplay between female hormones and migraine can be a challenging area to navigate since issues relating to pregnancy, contraception and the menopause are often out of the neurology comfort zone. This review aims to help the neurologist to manage women with migraine, from menarche to menopause.

Bone health in estrogen-free contraception.

Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.

Hormonal Contraceptives and Mood: Review of the Literature and Implications for Future Research.

PURPOSE OF REVIEW: We examine recent studies that investigate the effects of hormonal contraception on mood in different populations of women, including women in the general population and women with diagnosed psychiatric and gynecologic disorders. We address the mechanisms of several types of hormonal contraceptives and assess how these may affect mood and gynecologic disorders. RECENT FINDINGS: The effects of hormonal contraceptives seem to be most relevant in selected subsets of women, as they may promote improved mental health in particular psychiatric disorders such as PMDD. Currently, there is no consistent evidence for negative effects of most hormonal contraceptives in the general population. Even though some studies reveal that certain individuals appear susceptible to negative mood effects from some forms of hormonal contraceptives, more research is needed to better identify these susceptible individuals.

Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus.

BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In April 2014, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. The initial search also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. No new trials were eligible in 2014. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome. Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta-analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36). Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38). Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73). Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17ß-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI -0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods. We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal).

Influence of female hormones on fascia elasticity: An elastography study.

The aim of this study was to examine the influence of hormonal changes during the menstrual cycle on deep fasciae. A total of 29 women, 17 users, and 12 nonusers of hormonal contraceptives were examined clinically and by ultrasound, including shear wave elastography, at two phases of the menstrual cycle. The thickness and elasticity of the fascia lata, thoracolumbar fascia, and plantar fascia were measured, compared between hormonal contraceptive users and nonusers, and correlated with clinical data. There were statistically significant differences between users and nonusers of hormonal contraceptives: the thoracolumbar fascia was thicker in nonusers (P = 0.011), and nonusers had higher maximal and mean stiffnesses of the fascia lata (P = 0.01 and 0.0095, respectively). Generally, nonusers had a higher body mass index (BMI). The elasticity of the thoracolumbar and the plantar fasciae did not differ significantly between the groups. We found no correlation between thickness and elasticity in the fasciae. There were no statistically significant differences in hypermobility, cephalgia, or dysmenorrhea between users and nonusers of hormonal contraceptives. The results of this pilot study suggest that deep fasciae can be evaluated by shear wave elastography. Nonusers of contraceptives had greater stiffness of the fascia lata and higher BMI. Clin. Anat. 32:941-947, 2019. © 2019 Wiley Periodicals, Inc.

Comparing cervical mucus changes in response to an oral progestin or oestrogen withdrawal in ovarian-suppressed women: a clinical pilot.

Purpose: Prior studies evaluating the effect of administered progestogens on peak cervical mucus have not controlled for the influence of endogenous hormones. To address this, we treated women with a gonadotropin-releasing hormone (GnRH) agonist to suppress the hypothalamus-pituitary-ovarian (HPO) axis and used transdermal oestradiol replacement to stimulate peak cervical mucus and then evaluated the effects of an oral progestin or oestradiol withdrawal. Materials and methods: We used a crossover design to examine cervical mucus changes in women receiving transdermal oestradiol replacement following intramuscular administration of leuprolide acetate. After increasing oestradiol patches to mid-cycle levels, subjects were assigned to either 0.35 mg oral norethindrone with continuation of the patches (NET) or oestradiol withdrawal by patch removal (E2WD). We collected serum and cervical mucus samples at 0, 2, 4, 6, 22 and 24 h following the intervention. Results: We analysed 12 cycles (6 NET, 6 E2WD) from three subjects. Baseline cervical mucus scores were favourable to sperm penetration [NET median 11, interquartile range (9-12), E2WD 13 (12-13)]. Two hours after removal of oestradiol patch or administration of norethindrone, cervical mucus scores declined [NET 8.5 (4-9), E2WD 10.5 (10-12)]. Low cervical mucus scores persisted at 24 h with NET [8.0 (7-8)] but not E2WD [10.5 (8-11)]. Conclusions: We observed a rapid decline in cervical mucus Insler scores following administration of a single dose of oral norethindrone, and scores remained lower and unfavourable through 24 h. Oestradiol withdrawal did not result in similar unfavourable changes.

Effect of sex, menstrual cycle phase, and monophasic oral contraceptive pill use on local and central arterial stiffness in young adults.

Arterial stiffness is associated with increased cardiovascular disease risk. Previous sex-based investigations of local and central stiffness report inconsistent findings and have not controlled for menstrual cycle phase in women. There is also evidence that sex hormones influence the vasculature, but their impact on arterial stiffness across a natural menstrual (NAT) or oral contraceptive pill (OCP) cycle has been understudied. This study sought to 1) examine potential sex differences in local and central stiffness, 2) compare stiffness profiles between NAT and OCP cycles, and 3) investigate the relationship between duration of OCP use and arterial stiffness. Sex hormone concentrations, ß-stiffness index (local stiffness), and carotid-femoral pulse wave velocity [cfPWV (central stiffness)] were assessed in 53 healthy adults (22 ± 3 yr old, 20 men, 15 NAT women, and 18 OCP women). All participants were tested three times: men on the same day and time 1 wk apart, NAT women in menstrual, midfollicular and luteal phases of the menstrual cycle, and OCP women in placebo, early active and late active pill phases. ß-Stiffness was higher in men than NAT and OCP women ( P < 0.001), whereas cfPWV was similar between groups ( P = 0.09). ß-Stiffness and cfPWV did not differ across or between NAT and OCP cycles ( P > 0.05 for both) and were not associated with duration of OCP use (ß-stiffness: r = 0.003, P = 0.99; cfPWV: r = -0.26, P = 0.30). The apparent sex differences in local, but not central, stiffness highlight the importance of assessing both indexes in comparisons between men and women. Furthermore, fluctuating sex hormone levels do not appear to influence ß-stiffness or cfPWV. Therefore, these stiffness indexes may need to be assessed during only one cycle phase in women in future investigations. NEW & NOTEWORTHY We observed higher local, but not central, arterial stiffness in men than women. We also demonstrated that there are no differences in arterial stiffness between naturally cycling women and women who use monophasic oral contraceptive pills, and that the duration of oral contraceptive pill use does not influence arterial stiffness.

Brachial artery endothelial function is stable across a menstrual and oral contraceptive pill cycle but lower in premenopausal women than in age-matched men.

Sex hormone concentrations differ between men, premenopausal women with natural menstrual cycles (NAT), and premenopausal women using oral contraceptive pills (OCP), as well as across menstrual or OCP phases. This study sought to investigate how differences in sex hormones, particularly estradiol, between men and women and across cycle phases might influence brachial artery endothelial function. Fifty-three healthy adults (22 ± 3 yr, 20 men, 15 NAT women, and 18 second-, third-, or fourth-generation OCP women) underwent assessments of sex hormones and endothelial [flow-mediated dilation (FMD) test] and smooth muscle [nitroglycerin (NTG) test] function. Men were tested three times at 1-wk intervals, and women were tested three times throughout a single menstrual or OCP cycle (NAT: menstrual, midfollicular, and luteal phases and OCP: placebo/no pill, "early", and "late" active pill phases). Endogenous estradiol concentration was comparable between men and women in their NAT menstrual or OCP placebo phase ( P = 0.36) but increased throughout a NAT cycle ( P < 0.001). Allometrically scaled FMD did not change across a NAT or OCP cycle but was lower in both groups of women than in men ( P = 0.005), whereas scaled NTG was lower only in NAT women ( P = 0.001). Changes in estradiol across a NAT cycle were not associated with changes in relative FMD ( r2 = 0.01, P = 0.62) or NTG ( r2 = 0.09, P = 0.13). Duration of OCP use was negatively associated with the average relative FMD for second-generation OCP users only ( r = -0.65, P = 0.04). Our findings suggest that brachial endothelial function is unaffected by cyclic hormonal changes in premenopausal women but may be negatively impacted by longer-term use of second-generation OCPs. NEW & NOTEWORTHY We demonstrate that brachial artery flow-mediated dilation does not change across a menstrual or oral contraceptive pill cycle in premenopausal women but is lower in women than in men. Although unaffected by within-cycle changes in estradiol, brachial flow-mediated dilation is negatively correlated with duration of oral contraceptive pill use for second-generation pills.

Hormonal contraceptive affects heterosexual but not homosexual behavior in free-ranging female Japanese macaques over 17 mating seasons.

We assessed the effect of a progestin-based contraceptive treatment (chlormadinone acetate) on female heterosexual and homosexual behaviors in a free-ranging group of Japanese macaques (Macaca fuscata) living at Arashiyama-Kyoto, Central Japan. The data included estimated intensity of fertility cues, sexual solicitations and mounting behaviors collected daily during 17 consecutive mating seasons (1995-2012) from 159 females. Females that were on contraception: (1) exhibited less intense cues of putative fertility and for shorter periods; (2) were solicited by fewer males, and those males that did solicit them did so less often (i.e., lower heterosexual attractivity); (3) solicited fewer males and when they did perform sexual solicitations they did so less often (i.e., lower heterosexual proceptivity); (4) engaged in shorter heterosexual consortships with fewer male partners (i.e., lower heterosexual receptivity), compared with females that were not on contraception. In contrast, contraceptive treatment had no significant effect on the prevalence, occurrence, frequency, or duration of female homosexual behaviors. Even though heterosexual and homosexual behaviors can both be considered sexual in character and under hormonal control, our results suggested they are, to some extent, dissociable. Because females engaging in homosexual interactions showed less intense cues of putative fertility than those engaging in heterosexual interactions, regardless of contraceptive treatment, we argued that the hormonal threshold required for the expression of heterosexual behavior by females was associated with elevated sex hormones levels compared to homosexual behavior. We discussed the hormonal correlates of sexual behavior and partner preferences in Japanese macaques.