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Hyperandrogenism in women, such as polycystic ovary syndrome, ovarian hyperthecosis, congenital adrenal hyperplasia, and androgen-secreting tumors, are all associated with increased prevalence of cardiovascular risk factors that include type 2 diabetes, hypertension, dyslipidemia, and metabolic syndrome. However, it is not clear whether this also implies enhanced risk of cardiovascular disease and mortality. Furthermore, the involvement of obesity and menopausal status for cardiometabolic risk in these women has not been elucidated. Based on the most recent systematic reviews and meta-analyses, this review summarizes the latest scientific evidence. To conclude, hyperandrogenism in premenopausal women is associated with enhanced prevalence of cardiovascular risk factors, as well as increased risk of cardiovascular disease and mortality, independently of body mass index. In contrast, elevated cardiovascular risk factors and increased risk of myocardial infarction and stroke in hyperandrogenic postmenopausal women are dependent on obesity. Furthermore, the overall risk of cardiovascular disease and coronary artery disease in hyperandrogenic postmenopausal women is similar to controls. The reason for a reduced cardiometabolic risk after menopause in hyperandrogenic women compared to nonhyperandrogenic women is not clear. It can be speculated that the difference in endocrine balance and metabolic status between women with and without hyperandrogenism might decrease after menopause because hyperandrogenism usually improves with age, whereas menopausal transition itself is associated with androgen dominance and abdominal obesity. Although we have gained increased knowledge about cardiometabolic risks in women with hyperandrogenism, it must be acknowledged that the quality of data is overall low. More research is needed, especially longer and larger follow-up studies in women with hyperandrogenism of different etiologies and phenotypes.

Emerging evidence indicates that testosterone, which can increase muscle mass and strength, stimulates erythropoiesis, promotes competitive behaviour, and enhances the physical performance of women. Indeed, the levels of testosterone within the normal female range are related to muscle mass and athletic performance in female athletes. Furthermore, among these athletes, the prevalence of hyperandrogenic conditions, including both polycystic ovary syndrome and rare differences/disorders of sex development (DSD), which may greatly increase testosterone production, are elevated. Thus, if the androgen receptors of an individual with XY DSD are functional, her muscle mass will develop like that of a man. These findings have led to the proposal that essential hyperandrogenism is beneficial for athletic performance and plays a role in the choice by women to compete in athletic activities. Moreover, a recent randomized controlled trial demonstrated a significant increase in the lean mass and aerobic performance by young exercising women when their testosterone levels were enhanced moderately. Circulating testosterone is considered the strongest factor to explain the male advantage in sport performance, ranging between 10 and 20%. It appears to be unfair to allow female athletes with endogenous testosterone levels in the male range (i.e. 10–20 times higher than normal) to compete against those with normal female androgen levels. In 2012, this consideration led international organizations to establish eligibility regulations for the female classification in order to ensure fair and meaningful competition, but the regulations are controversial and have been challenged in court.

Stanniocalcin-1 (STC-1) is a pro-survival factor that protects tissues against stressors, such as hypoxia and inflammation. STC-1 is co-expressed with the endometrial receptivity markers, and recently endometrial STC-1 was reported to be dysregulated in endometriosis, a condition linked with endometrial progesterone resistance and inflammation. These features are also common in the endometrium in women with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. Given that women with PCOS present with subfertility, pregnancy complications, and increased risk for endometrial cancer, we investigated endometrial STC-1 expression in affected women. Endometrial biopsy samples were obtained from women with PCOS and controls, including samples from overweight/obese women with PCOS before and after a 3-month lifestyle intervention. A total of 98 PCOS and 85 control samples were used in immunohistochemistry, reverse-transcription polymerase chain reaction, or in vitro cell culture. STC-1 expression was analyzed at different cycle phases and in endometrial stromal cells (eSCs) after steroid hormone exposure. The eSCs were also challenged with 8-bromo-cAMP and hypoxia for STC-1 expression. The findings indicate that STC-1 expression is not steroid hormone mediated although secretory-phase STC-1 expression was blunted in PCOS. Lower expression seems to be related to attenuated STC-1 response to stressors in PCOS eSCs, shown as downregulation of protein kinase A activity. The 3-month lifestyle intervention did not restore STC-1 expression in PCOS endometrium. More studies are warranted to further elucidate the mechanisms behind the altered endometrial STC-1 expression and rescue mechanism in the PCOS endometrium.

Many studies report on the association between 2D:4D, a putative marker for prenatal testosterone exposure, and economic preferences. However, most of these studies have limited sample sizes and test multiple hypotheses (without preregistration). In this study we mainly replicate the common specifications found in the literature for the association between the 2D:4D ratio and risk taking, the willingness to compete, and dictator game giving separately. In a sample of 330 women we find no robust associations between any of these economic preferences and 2D:4D. We find no evidence of a statistically significant relation for 16 of the 18 total regressions we run. The two regression specifications which are statistically significant have not previously been reported and the associations are not in the expected direction, and therefore they are unlikely to represent a real effect.

Interleukin 33 (IL-33) signaling regulates most of the key processes of pregnancy, including decidualization, trophoblast proliferation and invasion, vascular remodeling, and placental growth. Accordingly, dysregulation of IL-33, its membrane-bound receptor (ST2L, transducer of IL-33 signaling), and its soluble decoy receptor (sST2, inhibitor of IL-33 signaling) has been linked to a wide range of adverse pregnancy outcomes that are common in women with obesity and polycystic ovary syndrome, that is, conditions associated with hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. To reveal if androgens and insulin might modulate uteroplacental IL-33 signaling, we investigated the effect of dihydrotestosterone (DHT) and/or insulin on the expression of ST2Land sST2(along with the activity of their promoter regions), IL-33and sIL1RAP(heterodimerization partner of sST2), during in vitrodecidualization of endometrial stromal cells from 9 healthy women. DHT and insulin markedly upregulated sST2 secretion, in addition to the upregulation of its messenger RNA (mRNA) expression, while the proximal ST2promoter, from which the sST2transcript originates, was upregulated by insulin, and in a synergistic manner by DHT and insulin combination treatment. On the other hand, sIL1RAPwas slightly downregulated by insulin and IL-33mRNA expression was not affected by any of the hormones, while ST2LmRNA expression and transcription from its promoter region (distal ST2 promoter) could not be detected or showed a negligibly low level. We hypothesize that high levels of androgens and insulin might lead to subfertility and pregnancy complications, at least partially, through the sST2-dependent downregulation of uteroplacental IL-33 signaling.

ABSTRACTBackground: This exploratory analysis was conducted to characterize the level of HPV types 6/11 antibodies in peripartum maternal blood and in cord blood of infants born to women who received 9-valent HPV (9vHPV) vaccine or quadrivalent HPV (qHPV) vaccine in a pivotal efficacy study (V503-001, NCT 00543543).Methods: A total of 21 mother-infant pairs had evaluable HPV 6/11 results available for analysis. HPV6/11 antibodies were assessed using competitive Luminex immunoassay. The distribution of the ratios of infant to mother anti-HPV antibodies (i.e., infant-anti-HPV/mother- anti-HPV) was summarized.Results: All mothers and infants were seropositive to HPV 6 and HPV 11. Anti-HPV 6/11 geometric mean titers (GMTs) in peripartum maternal blood and in cord blood of infant born to study participants were highly correlated. A 100% of infants born to seropositive mothers were also seropositive. The GMT ratios of peripartum maternal blood vs. those in cord blood were HPV 6: 1.23 [0.43, 3.49] and HPV 11: 1.29 [0.54, 3.07] in the 9vHPV vaccine group and HPV 6: 1.33 [0.41, 4.29] and HPV 11: 1.19 [0.45, 3.13] in the qHPV vaccine group, respectively.Conclusions: These results indicate that antibodies induced by the 9vHPV vaccine cross the placenta, which could potentially be beneficial against HPV6/11 infection and related disease such as recurrent respiratory papillomatosis.

Human cytomegalovirus (HCMV) has been detected in various types of tumors. We studied the prevalence of HCMV in ovarian cancer and its relation to clinical outcome. Paraffin-embedded tissues obtained prospectively from 45 patients with ovarian cancer and 30 patients with benign ovarian cystadenoma were analyzed for expression of HCMV immediate-early protein (IE) and HCMV tegument protein (pp65) by immunohistochemistry. Plasma was analyzed for HCMV serology. HCMV-IgG levels were higher in patients with ovarian cancer or benign cystadenoma than in age-matched controls (P = .002, P < .0001, respectively). HCMV IgM was detected in 12% of ovarian cancer patients and 3% of patients with benign tumors but was absent in controls. In patients with ovarian cancer, higher IgG levels were associated with better outcomes (P = .04). Extensive HCMV-IE protein expression was detected in 75% of ovarian cancers and 26% of benign tumors; pp65 was detected in 67% of ovarian cancers and 14% of benign tumors. A higher grade of HCMV infection was associated with higher stage of disease. Extensive HCMV-pp65 expression was associated with shorter median overall survival than focal expression (39 versus 42.5 months, P = .03).At study closure, 58% of ovarian cancer patients with focal pp65 expression were alive versus 27% of patients with extensive pp65 expression (P = .03). Thus, HCMV proteins are detected at different levels in ovarian tumors and benign cystadenomas. Ovarian cancer patients with focal HCMV-pp65 expression in their tumors and high IgG levels against HCMV lived longer, highlighting a need for in-depth studies of the oncomodulatory role of HCMV in ovarian cancer.

Polycystic ovary syndrome (PCOS) is associated with increased risk of endometrial cancer. This is usually explained by chronic anovulation and deficient progesterone activity. However, the role of progesterone receptors (PRs) in endometrial proliferation is unclear.

BackgroundThe role of endogenous androgens for body composition and physical performance in women athletes is still not elucidated.AimTo examine the serum androgen profile in relation to body composition and physical performance in women Olympic athletes and to compare endocrine variables and body composition to controls.Study designCross-sectional study, conducted between 2011 and 2015 at the Women’s Health Research Unit, Karolinska University Hospital, Stockholm.MethodsSwedish women Olympic athletes (n=106) and age-matched and body mass index-matched sedentary controls (n=117) were included in the study. Blood sampling was performed in a rested, fasting state for the measurement of serum androgens and their metabolites by liquid chromatography–tandem mass spectrometry. Body composition was determined by dual-energy X-ray absorptiometry (controls n=100, athletes n=65). The athletes performed standardised performance tests (n=59) (squat jump (SJ) and countermovement jump (CMJ).ResultsThe athletes demonstrated significantly higher levels of the precursor androgens dehydroepiandrosterone (DHEA) and 5-androstene-3β, 17β-diol (5-DIOL) and the metabolite etiocholanolone glucuronide (Etio-G), significantly lower levels of estrone (p<0.05, respectively), higher bone mineral density (p<0.001) and more lean mass (p<0.001) compared with controls. Serum levels of DHEA, 5-DIOL and Etio-G correlated positively to lean mass variables and physical performance in the athletes. DHEA and lean mass legs explained 66% of the variance in SJ, whereas lean mass explained 52% of the variance in CMJ.ConclusionsThe present data suggest that endogenous androgens are associated with a more anabolic body composition and enhanced performance in women athletes. These results are of importance for the current discussion regarding hyperandrogenism in women athletes.

Context:There is a lack of knowledge about how oral contraceptives may affect sexual function.Objective:To determine whether there is a causal effect of oral contraceptives on sexuality. We hypothesized that a widely used pill impairs sexuality.Design:A double-blind, randomized, placebo-controlled trial. Enrollment began in February 2012 and was completed in August 2015.Setting:Karolinska University Hospital, Stockholm, Sweden.Participants:A total of 340 healthy women, aged 18–35 years, were randomized to treatment, and 332 completed the study.Interventions:A combined oral contraceptive (150 μg levonorgestrel and 30 μg ethinylestradiol) or placebo for 3 months of treatment.Main Outcome Measures:The primary outcome was the aggregate score on the Profile of Female Sexual Function (PFSF). Secondary outcomes were the seven domains of the PFSF, the Sexual Activity Log, and the Personal Distress Scale.Results:Overall sexual function was similar in women in the oral contraceptive and placebo groups. The PFSF domains desire (−4.4; 95% confidence interval [CI], −8.49 to −0.38; P= .032), arousal (−5.1; 95% CI, −9.63 to −0.48; P= .030), and pleasure (−5.1; 95% CI, −9.97 to −0.32; P= .036) were significantly reduced in comparison to placebo, whereas orgasm, concern, responsiveness, and self-image were similar between groups. The mean frequency of satisfying sexual episodes and personal distress were also similar between groups.Conclusions:This study shows no negative impact of a levonorgestrel-containing oral contraceptive on overall sexual function, although three of seven sexual function domains were adversely affected.

Context:Polycystic ovary syndrome (PCOS) is a common cause of anovulation. It may also negatively affect the endometrium, which could lead to implantation failure and proliferative aberrations.Objective:Our objective was to study sex hormone receptors in the endometrium of women with PCOS.Design:This is a cross-sectional study and lifestyle intervention.Setting:Clinical and laboratory research unit was undertaken at a university hospital.Participants:Twenty overweight/obese women fulfilling all three PCOS criteria (anovulation, hyperandrogenism, and polycystic ovaries), 10 body mass index–matched regularly menstruating controls, 11 normal-weight women with PCOS, and 11 normal-weight controls.Intervention:Intervention for this study included dietary management and physical exercise.Main Outcome Measures:mRNA levels and immunostaining of estrogen receptor α (ERα) and β (ERβ), nongenomic estrogen receptor α36 (ERα36), and G-protein–coupled estrogen receptor-1 (GPER), and the androgen receptor (AR) on cycle days 6–8 and cycle days 21–23.Results:Before intervention, mRNA levels of ERα, ERα36, and the ERα/ERβ mRNA ratio were lower in proliferative endometrium of overweight/obese PCOS women compared with controls (P< .05). After intervention, ERα protein and the ERα/ERβ protein ratio in proliferative endometrium increased and were higher in PCOS women with improved menstrual function than in those without improvement (P< .05). In the subgroup of PCOS women with restored ovulation, only higher protein levels of GPER were found in secretory endometrium (P< .01). However, PCOS women who remained anovulatory had higher protein levels of ERα, GPER, and AR on cycle days 21–23 than controls (P< .05).Conclusions:Lifestyle intervention alters, but does not fully restore, ER and AR expression in proliferative and secretory endometrium of obese women with PCOS.

This study aims to assess use of hormone therapy (HT) after cervical cancer treatment in women of premenopause age.

Thyroid gland dysfunction is associated with menstrual cycle disturbances, infertility, and increased risk of miscarriage, but the mechanisms are poorly understood. However, little is known about the regulation of these receptors in the uterus. The aim of this study was to determine the effects of long-term treatment with steroid hormones on the expression, distribution, and regulation of the receptors for thyrotropin-releasing hormone (TRHR) and thyroid-stimulating hormone (TSHR), thyroid hormone receptor 12 (THR12), and THR1 in the uterus of surgically menopausal monkeys.

Tibolone is an alternative hormone treatment for managing climacteric symptoms in postmenopausal women. The aim of this study was to determine the effects of long-term tibolone (TIB) treatment in comparison with conventional hormone therapy on the expression and distribution of estrogen receptor (ER) , ER-, G-protein–coupled ER-1 (GPER), progesterone receptor (PR) A, PRB, androgen receptor (AR), and syndecan-1 in the macaque uterus.

The aim of this study was to investigate whether tapering down of combined estrogen plus progestogen therapy (EPT) reduced the recurrence of hot flashes and resumption of therapy compared with abrupt discontinuation. A secondary aim was to evaluate whether health-related quality of life (HRQoL) was affected after discontinuation of EPT and to investigate the possible factors predicting resumption of EPT.

Our aim was to investigate the effects of the addition of testosterone to estrogen compared with those of estrogen alone on the expression and distribution of sex hormone receptors in glands and stroma of the endometrium of postmenopausal women.

During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast. Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy.

The aim of this study was to determine the effects of the isopropanolic extract of black cohosh (Remifemin) on mammographic breast density and breast epithelial proliferation in healthy, naturally postmenopausal women with climacteric symptoms.

Objective: Data concerning bone mineral density (BMD) in bulimia nervosa are contradictory and include both low and normal values. The aim of the present study was to elucidate possible endocrine-and nutrition-related factors predicting BMD in bulimic women.Design: Cross-sectional study.Methods: Seventy-seven bulimic patients and 56 age- and body mass index (BMI)-matched healthy controls were examined with respect to BMD (dual energy X-ray absorptiometry) and to serum levels of hormones and metabolic factors.Results: Bulimics had significantly lower spinal BMD and higher frequency of osteopenia in the total body than controls. Furthermore, bulimic women had significantly lower levels of estradiol-17β and free thyroxine and significantly higher cortisol levels compared with controls. Among the bulimics, 31.2% had present menstrual disturbance, 51.9% had a history of amenorrhea and 23.4% had previous anorexia nervosa. Subgroups of bulimics with a history of amenorrhea and previous anorexia nervosa had significantly lower total and spinal BMD than controls, whereas those without such history did not differ from the controls. In univariate analysis, a history of amenorrhea, cortisol, testosterone, previous anorexia nervosa, and BMI showed significant associations with spinal BMD. Multiple regression analysis including all significant variables revealed previous anorexia nervosa to be the strongest determinant of spinal BMD, accounting for 34% of the variance, while associations between endocrine factors and BMI disappeared.Conclusions: Low bone mass in bulimics may be explained by previous anorexia nervosa, whereas endocrine variables related to BMD seem to be secondary determinants that are dependent on previous anorexia nervosa and BMI.

To explore possible changes in adrenal steroid metabolism and androgenic-anabolic status in female endurance athletes as a mechanism for their hypercortisolism.

Treatment with androgens such as testosterone has a number of salutary effects on postmenopausal women, including greater energy, improved sexual function, preservation of bone mass, and possibly a protective effect on the breast. There is concern, however, that excessive androgen may lead to an insulin-resistant state. This study addressed the issue of insulin sensitivity using testosterone undecenoate (TU), an orally active preparation with only minor liver-related side effects. Participants were 63 naturally postmenopausal women in good general health, 2 of whom were obese. The women were randomly assigned to receive 40 mg testosterone (T) in the form of TU every other day, 2 mg estradiol (E) valerate daily, or both treatments (TE), all for 3 months. The euglycemic hyperinsulinemic clamp technique served to estimate insulin sensitivity.

BackgroundAndrogens have anabolic effects that may contribute to enhanced physical performance and a decreased risk of injury in athletes. The role of endogenous androgens for athletic performance in female athletes is not yet fully elucidated.ObjectiveTo examine the profile of serum androgens in relation to body composition and physical performance in female Olympic athletes and compared to sedentary controls.DesignCross-sectional study, recruitment 2011–2015.SettingThe Women's Health Research Unit, Karolinska University Hospital.Participants106 female Swedish Olympic athletes (summer and winter sports) and 117 controls (maximum 2 hours training per week, no prior participation in elite-level sports).AssessmentParticipants were examined at one occasion at rest and in a fasting state for blood sampling. Serum androgen levels were established by liquid chromatography-mass spectrometry. Body composition was evaluated by DXA. Physical performance tests (Squat jump (SJ), Counter Movement Jump (CMJ)) were made at the Sports Institute, Boson, as part of the “Physical Profile” offered by the Swedish Olympic Committee.Main Outcome MeasurementsThe profile of serum androgens, body composition, physical performance.ResultsFemale Olympic athletes demonstrated significantly higher androgen levels of dehydroepiandrosterone (DHEA) and androstandiol (5-ADIOL), lower levels of estrone, and a more anabolic body composition compared to controls. Athletes in power sports had significantly higher bone mineral density compared to endurance and technical athletes, whereas endurance athletes had the highest values of lean mass. Serum levels of DHEA and 5-ADIOL correlated positively to lean mass in female athletes (R=0.25–0.33). Furthermore, DHEA, 5-ADIOL and dihydrotestosterone correlated positively to CMJ and SJ in the athletes (R=0.27–0.39).ConclusionsWe suggest that endogenous androgens contribute to a more anabolic body composition and increased physical performance in female athletes. Furthermore, the anabolic effect on body composition could play a role for the risk of injury.

Estrogen supports urothelial defense against infection by increasing the expression of antimicrobial peptides and by protecting epithelial integrity.