Progress in genome-wide association studies of age at natural menopause.

Menopause is not only the end of reproductive life, it is also related to diseases such as hyperlipidaemia, atherosclerotic cardiovascular disease, osteoporosis and breast cancer. Traditional epidemiological studies have found that heredity is the main determinant of age at natural menopause (ANM). Early studies on genetic factors were limited to candidate gene studies. Menopause age is not inherited by a single gene, but is the result of multiple gene effects. With the development of genomic technology, the Reproductive Genetics Consortium conducted several genome-wide association studies on ANM in people of European descent, and found that defects in DNA damage repair pathways were the main genetic mechanism. In recent years, due to the ethnic heterogeneity of ANM, there has been further development of global studies into multi-ethnic and trans-ethnic genome-wide association studies. Further genetic and epidemiological studies, including polygenetic score and genetic mechanism research, should be conducted to investigate the pathogenesis and mechanism with respect to menopause and its related diseases.

Prevalence of metabolic syndrome and its components in Chinese women with premature ovarian insufficiency.

OBJECTIVES: To assess the prevalence of metabolic syndrome (MetS) and its components in Chinese women with premature ovarian insufficiency (POI) and to explore the metabolic profile of Chinese women with POI. METHODS: 118 POI women aged 20-38 years and 151 age-and-BMI-matched control women were recruited. Measurements included body height, weight, waist circumference (WC), hip circumference (HC), blood pressure, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG) and fasting insulin (FINS). Prevalence and components of MetS and metabolic indices were compared between the two groups. RESULTS: The prevalence of MetS in POI women and age-and-BMI-matched control women was 16.9% and 11.3%, respectively, which was not significantly different (p > .05). The prevalence of hypertriglyceridemia and high fasting glucose was significantly higher in POI than control (17.8% vs. 9.3%, p = .039; 16.9% vs. 6.6%, p = .008), without significant differences in the prevalence of other components of MetS (p > .05). The levels of TG, FINS, and HOMA-IR in POI were significantly higher than in control (p < .05) but without significant differences in WC, WHR, SBP, DBP, TC, HDL-C, LDL-C, and FPG (p > .05). HOMA-IR was positively correlated with WC, DBP, TG, and FPG and negatively correlated with HDL-C in both POI women and control (p < .05). CONCLUSIONS: POI women presented with more unfavorable cardiovascular risk factors (higher prevalence of hypertriglyceridemia and high fasting glucose; higher TG, FINS, and HOMA-IR). So, women diagnosed with POI should always be covered with special care of metabolic profile.

Prevalence of diminished ovarian reserve in Chinese women with follicular cysts and menstrual disorders.

OBJECTIVES: To assess the prevalence of diminished ovarian reserve (DOR) in Chinese women with follicular cysts and menstrual disorders and relationship to hormonal markers. METHODS: 117 women with follicular cysts and menstrual disorders, aged 24 ∼ 53 (39.19 ± 6.61) years; measurements of height, weight, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, progesterone (Po), prolactin (PRL), total testosterone, AMH, follicular cyst diameter, endometrial thickness. Three age groups were compared: 1) 21 ∼ 30 years, 2) 30 ∼ 40 years, 3) > 40 years. RESULTS: Total prevalence of DOR 86.3%, in the groups 50%, 81.6%, and 98.4%, in group-3 significantly higher than in group-1 and 2. 34.2% of the 117 patients complained of cessation of regular menstruations or amenorrhea, 65.8% of abnormal uterine bleeding. Follicular cysts disappeard in cycle-1 for 98 (83.8%) and in cycle-2 for 117 (100%) patients. AMH decreased with age, significantly different between the three groups. Total testosterone in group-1 and 2 was significantly higher than in group-3. In total AMH had a negative correlation with age and E2 (p < 0.01) and positive correlation with total testosterone (p < 0.05). CONCLUSIONS: Assessing ovarian reserve with follicular cysts and menstrual disorders is important because often pointing to DOR. The overall prevalence of DOR was high; even young women (<40 years) with follicular cysts and menstrual disorders had a low level of AMH. So AMH can be used as a marker to define DOR with higher sensitivity than other markers like FSH and E2. Primarily, these results only apply to Chinese women and should be confirmed in further studies.

Sexual function in Chinese women with different clinical phenotypes of polycystic ovary syndrome.

Objective: To investigate sexual function stratified according to four clinical phenotypes of polycystic ovary syndrome (PCOS) and its association with clinical and quality of life parameters, and to compare these with healthy controls in Chinese women with PCOS. Methods: A cross-sectional study was designed in 1000 PCOS women and 500 control women aged 18-45 years. PCOS women were grouped into four clinical phenotypes according to the Rotterdam Criteria. FSFI (Female Sexual Function Index), SF-12 (the 12-item short form health survey) and clinical and hormonal characteristics likely to affect sexual function were determined. Results: 809 PCOS women and 385 control women with complete parameters were evaluated after screening. Phenotype A had a lower total FSFI mean score (23.14 ± 3.22) compared with phenotype D and control group (p < 0.05). The control group had the highest total FSFI mean score (24.98 ± 3.78). For the percentage at risk of sexual dysfunction, phenotype A (87.5%) and phenotype B (82.46%) had a higher risk of female sexual dysfunction (FSD) than that in phenotype C (75.34%), phenotype D (70.56%) and control group (61.30%) (p < 0.05). SF-12 mental domain scores were significantly lower in phenotypes A and B compared with phenotypes C and control group (p < 0.05). Infertility treatment, bioavailable testosterone, psychological factors, age and waist circumference presented negative correlation with female sexual function. Conclusions: The risk of FSD in PCOS women seemed to be associated with PCOS clinical phenotypes. The classical PCOS phenotype with oligo-ovulation and hyperandrogenism had a higher risk of sexual dysfunction.

Diagnostic value of anti-Müllerian hormone combined with androgen-levels in Chinese patients with polycystic ovary syndrome.

OBJECTIVE: To establish a cutoff level of AMH which could help for the diagnosis of PCOS, to investigate the predictive value of AMH combined with androgens in Chinese women to diagnose PCOS. MATERIALS AND METHODS: This is a prospective case control study, 550 women recruited (aged 20-40 years), in which 450 PCOS women recruited according to the Rotterdam criteria and 100 non-PCOS women in the control group were from the women for the pregnancy preparation examination. AMH were measured by the Elecsys AMH Plus immunoassay. Androgens and other sex hormone were measured. The validity of AMH toward the diagnosis of PCOS, or AMH combined with total testosterone, free testosterone, bioavailable testosterone and androstenedione was estimated by receiver operating characteristic (ROC)curves, and correlations between paired variables was estimated by Spearman's rank correlation coefficient. RESULTS: The cutoff value of AMH in Chinese reproductive-age women with PCOS is 4.64 ng/mL, AUC under the curve is 0.938, with 81.6% sensitivity, and 92.0% specificity. Total testosterone, free testosterone, bioactive testosterone, and androstenedione are significantly higher in women with PCOS of reproductive age than in controls. The combination of AMH and free testosterone resulted in a higher AUC of 94.8%, with higher sensitivity (86.1%) and excellent specificity (90.3%) for the prediction of PCOS. CONCLUSION: The Elecsys AMH Plus immunoassay, with a cutoff of 4.64 ng/mL, is a robust method for identifying PCOM to aid in PCOS diagnosis. The combination of AMH and free testosterone resulted in a higher AUC of 94.8% for the diagnose of PCOS.

Effect on the cardiovascular independent risk factor lipoprotein(a) in overweight or obese PCOS patients with ethinyl-estradiol/drospirenone alone or plus orlistat.

OBJECTIVE: This study aimed to assess the effect on the cardiovascular independent risk factor Lipoprotein(a) [Lp(a)] in overweight or obese polycystic ovary syndrome (PCOS) patients with ethinyl-estradiol/drospirenone (EE/DRSP) alone or plus orlistat. METHODS: In this randomized controlled prospective study, 66 PCOS patients with overweight or obesity were matched according to age and BMI. All participants were randomly divided into two groups to receive EE/DRSP plus Orlistat (n = 33) or EE/DRSP alone (n = 33) for 3 months. Changes in cardiovascular risk factors including Lp(a), CRP, LDL-C, anthropometric assessments, variations in sex hormones related parameters, and in glucolipid metabolic index were evaluated after the intervention. RESULTS: Lp(a) and CRP were significantly decreased at 3 months only in the EE/DRSP plus Orlistat group. There were significant reductions in LDL-C, weight, BMI, waist circumference (WC), body fat percentage (BFP), FT in both groups compared to baseline. However, these reductions were significantly greater in EE/DRSP plus Orlistat group. The levels of HDL-C, TG, and SHBG significantly increased, while TT and LH significantly decreased in both groups over time. TC, FINS, FPG were not significantly changed in both groups after the intervention. CONCLUSIONS: This is the first study found that EE/DRSP plus Orlistat could significantly decrease Lp(a) in overweight or obese PCOS patients. This result can be assessed as particularly important, because Lp(a) is well-known as an independent risk factor predicting an increased risk of cardiovascular diseases (CVDs).

Menopausal symptoms among Chinese peri- and postmenopausal women: a large prospective single-center cohort study.

BACKGROUND: The prevalence and intensity of menopausal symptoms differ depending on ethnicity, culture, and country. Epidemiological data from China are scarce. OBJECTIVE: To compare the prevalence and severity of menopausal symptoms in peri- and postmenopausal Chinese women. METHODS: This was a prospective two year cohort study that included all eligible women from 31 Chinese provinces attending our 'Menopause Clinic', the first official specialized center in China. Structured questionnaires containing seven domains with 41 items in total were used to assess the following menopausal symptoms using descriptive analysis: negative mood, cognitive symptoms, sleep disorder, vasomotor symptoms (VMS), urogenital symptoms, autonomic nervous disorder, and limb pain/paresthesia. RESULTS: A total of 4063 women with a mean age of 50.53 ± 6.57 (n = 2107 perimenopausal and 1956 postmenopausal) participated. All menopausal symptoms were more severe in postmenopausal women (p<.05). Independent of menopausal status, urogenital symptoms, often combined with sexual problems, were the most common complaints (in prevalence and severity), followed by sleep disorder, cognitive symptoms (especially hypomnesia), negative mood, autonomic nervous disorder, limb pain/paresthesia and, as the rarest complaint, VMS. CONCLUSIONS: Urogenital symptoms among midlife Chinese women are common, frequently also in combination with sexual dysfunction, although many do not often complain about these in the first place. Postmenopausal women presented more prevalent and severe menopausal symptoms. In contrast to Western countries, VMS are rare among our population. A multidisciplinary approach and use of hormonal and non-hormonal therapies should be considered for these women.

Importance of active and passive smoking as one of the risk factors for female sexual dysfunction in Chinese women.

OBJECTIVE: To assess possible risk factors for female sexual dysfunction (FSD), aiming especially at smoking in China. METHODS: Female Sexual Function Index (FSFI) for assessing FSD; 621 women (24-75 years) divided into 'group FSD' (FSFI≤ 26.55) and 'group No FSD' (FSFI > 26.55). Univariate and multivariate analysis to detect potential risk factors for FSD. RESULTS: Active smoking was the strongest risk factor after multiple adjustments (OR= 6.226, 95%CI = 1.561 ∼ 24.822), but passive smoking also was significantly associated with a risk of FSD (OR = 1.887, 95%CI = 1.092 ∼ 3.260) (p < .05). Other risk factors included age (OR = 1.040, 95%CI = 1.005 ∼ 1.076), medical comorbidities (OR= 1.688, 95%CI =1.044 ∼ 2.729), postmenopausal stage (OR= 2.021, 95%CI = 1.073 ∼ 5.717), and dissatisfied marital relations (OR= 3.771, 95%CI = 1.768 ∼ 8.045). The prevalence of FSD for smokers regarding disorders of sexual arousal, orgasm and sexual satisfaction increased in active smokers; sexual desire disorder, sexual arousal disorder and pain in secondhand smokers (p < .05). CONCLUSION: The risk of FSD was closely related to depletion of ovarian function. Active smokers had the highest risk, but passive smoking also had a significant relationship to FSD. Although female smokers are rare in China, 'husband smoking' is frequent. Thus, our results should have significant healthcare consequences.

Sexual dysfunction in Chinese women at different reproductive stages and the positive effect of hormone replacement therapy in the early postmenopause.

OBJECTIVES: The aims of the study were to investigate female sexual dysfunction (FSD) at different reproductive stages and the effect on FSD of hormone replacement therapy (HRT). METHODS: Participants (N = 524) were divided into six groups according to the Stages of Reproductive Aging Workshop (STRAW + 10): reproductive age (R), early (ET)/late (LT) menopausal transition, early (EP)/late (LP) postmenopause and early postmenopause in women using HRT (EP-HRT; oestradiol sequentially combined with dydrogesterone). The Female Sexual Function Index (FSFI) was used to assess FSD. Univariate and multivariate logistic regression analysis was carried out to predict FSD risk factors. RESULTS: There was an increase in FSD in groups EP and LP, but not in groups R, ET and LT; most FSFI scores were lower in groups EP and LP than in groups R, ET and LT (p < .05). There was no difference in FSD between groups EP and LP, but lubrication and pain scores were higher in group EP (p < .05). The prevalence of FSD was lower in group EP-HRT; most FSFI scores were higher in group EP-HRT compared with group EP as control (p < .05). Further risk factors for FSD were identified as neutral and dissatisfied marital relations, lower educational level and smoking (p < .05). CONCLUSION: We report a clear association between deteriorating sexual function and increasing STRAW + 10 classification, suggesting the consequence of decreasing ovarian function. HRT containing 'natural hormones' was shown to have a beneficial effect on FSD. The results are reported here for the first time in Chinese women.

[Clinical evaluation of progestogens used in Menopausal Hormone Therapy (MHT)]. / Klinische Beurteilung der Gestagene in der Menopausalen Hormontherapie (MHT).

Clinical evaluation of progestogens used in Menopausal Hormone Therapy (MHT) Abstract. Primary indication for progestogens in MHT is to avoid estrogen-induced endometrial cancer. Progesteron has the least endometrial efficacy but is used increasingly (together with transdermal estradiol) because it is neutral in vascular and metabolic systems and possibly may have a lower risk of breast cancer. Comparable is dydrogesterone, the retro-isomer of progesterone, but with higher endometrial efficacy. However, also other progestogens (including tibolone) are used to take advantage of the androgenic, anti-androgenic and anti-mineralocorticoid "partial effects". Based on the results of the Women's Health Initiative Study the use of progestogens in MHT can cause an increased risk of breast cancer and coronary artery disease. Using different progestogens this is confirmed in various observational studies, which also suggest an increased progestogen-dependent risk of stroke. Since with every MHT early start can reduce cardiovascular risk or even act preventive, the decisive question remains, if there may be a screening regarding already known mechanisms for hormone-dependent development of breast cancer, at least for patients with increased risk of breast cancer. For this, new own research results are described.

PGRMC1 in animal breast cancer tissue and blood is associated with increased tumor growth with norethisterone in contrast to progesterone and dydrogesterone: four-arm randomized placebo-controlled xenograft study.

Progesterone receptor membrane component 1 (PGRMC1) is mediating strong breast cancer cell proliferation induced by certain synthetic progestogens which we have shown within already published in vitro studies. Aim was now to use an animal model, to compare tumor growth using progesterone and its isomer dydrogesterone with norethisterone, which elicited in our in vitro studies the strongest proliferating effect. For the first time, we wanted to investigate if growth can be correlated both with blood concentrations and tissue expression of PGRMC1 to identify if PGRMC1 could be a new tumor marker. Prospective, randomized, blinded, placebo-controlled four-arm study (45-50 days); PGRMC1-transfected or empty-vector T47D- and MCF7-xenotransplants were each treated with estradiol (E2) +placebo; E2 + progesterone; E2 + norethisterone; E2 + dydrogesterone; blood PGRMC1 assessed by a novel ELISA, tissue expression by immunohistochemistry. PGRMC1-transfected tumors further increased with E2 + norethisterone but not with E2-dydrogesterone or E2-progesterone. In both PGRMC1-xenograft groups (T47D, MCF7) with E2/norethisterone, the blood concentrations and tissue expression of PGRMC1 were higher than in all other 14 groups (p < .05), with positive significant correlation between blood PGRMCI concentrations and tissue PGRMC1 expression. In the presence of PGRMC1, certain progestogens could increase the growth of breast tumor, which now also should be tested in clinical studies.

Effect of laparoscopic endometrioma cystectomy on anti-Müllerian hormone (AMH) levels.

OBJECTIVE: To investigate temporary or long-term changes of AMH after laparoscopic endometrioma cystectomy and its dependency on characteristics of endometriomas. METHODS: One hundred and seventy-one women, open-labeled prospective study; five groups divided according age ≤/> 35, uni-/bilateral, cyst ≤/> 7 cm, coagulation/suture surgery, stage III/IV; between- and within-group analyses after 1, 3, 6, and 12 months. RESULTS: After 12 months, compared to pretreament, AMH decreased significantly for patients with bilateral cysts, cyst size >7 cm and endometriosis stage IV. In the between-group analysis all comparisons were significant, with exception of the surgery type. However, this was different performing the multiple linear regression analysis suggesting lower postoperative decrease using suturing technique. This analysis also showed higher age at pretreatment and bilateral cysts as risk factor for AMH decline. CONCLUSIONS: Effects of endometrioma cystectomy on AMH are dependent on characteristics of the endometrioma, showing long-term a decrease in patients with larger, bilateral cysts and in stage IV endometriosis, but only short-time decrease in smaller, unilateral cysts and stage III which sometimes also can fully recover in AMH production within one year. In our study suture compared to coagulation surgery was protective, i.e. may lead to lower postoperative AMH decline.

Early clinical features and risk factors for cesarean scar pregnancy: a retrospective case-control study.

The aim of this study was to investigate early clinical features and risk factors for cesarean scar pregnancy (CSP). Study group of 206 CSP patients out of 6853 women with early pregnancies, diagnosed from 2014 to 2016 was compared with a randomly selected control group of 412 patients. Early clinical features for CSP were vaginal bleeding (OR: 9.65; 95% CI: 5.67-16.41), lower abdominal pain (OR: 3.8; 95% CI: 1.52-9.54) and increased white blood cells (OR: 1.30; 95% CI: 1.12-1.50). Important risk factors for CSP were artificial abortion within the last pregnancy (OR: 4.13; 95% CI: 2.23-7.66), 0 ∼ 1 year and 2 ∼ 3 year interval between present and last pregnancy (OR: 2.27; 95% CI: 1.11-4.67 and OR: 2.15; 95% CI: 1.15-4.03). Pregnancy problems are important issues within the scope of 'Gynecological Endocrinology'. Vaginal bleeding and lower abdominal pain, although unspecific, could be early clinical symptoms of CSP, especially if main risk factors exist such as abortion within the last pregnancy and short interval to the last pregnancy. Knowing this can help for prevention and early diagnosis CSP which can reduce life-threatening complications such as massive hemorrhage and can avoid hysterectomy. Consequence also must be to avoid unwanted pregnancies by using effective contraception, especially in risk patients.

Ovarian tissue cryopreservation: prospective randomized study on thawed ovarian tissue viability to estimate the maximum possible delivery time of tissue samples.

Ovarian tissue cryopreservation is one of the most important methods to protect female fertility, but we just recently established the first central laboratory in China, now building a network with other hospitals. The aim was to estimate the thawed ovarian tissue viability and to explore the feasibility of short-distance transportation. Fifteen samples were obtained from each of 11 patients, i.e. in total 165 samples. One fresh sample was used for follicle counts, 14 punches were cryopreserved, thawed, and randomly divided into seven groups depending on the time after thawing: 0, 20, 40, 60, 80, 100, 120 min. Follicle counts, steroid hormones, and lactate levels were assessed. No significant differences for the three parameters of tissue viability comparing the seven groups were seen. The time can last up to two hours for the delivery of tissue samples from the laboratory to the surgery room. To our knowledge, this question has been tested for the first time systematically within a prospective randomized comparative study.

Oxidative stress indicators in Chinese women with PCOS and correlation with features of metabolic syndrome and dependency on lipid patterns.

OBJECTIVE: The aim was to investigate oxidative stress indicators in the blood of women with PCOS without and with metabolic syndrome (MS) and their dependency on lipids, comparing with healthy women. To our knowledge, this is the first study on this topic. METHODS: This was a cross-sectional study, and blood tests performed were double-blind. Within 3 months, 205 PCOS patients, from whom 55 also had MS, and 65 healthy women (control) were recruited. Malondialdehyde (MDA) was assessed as an important oxidative indicator, and superoxide dismutase (SOD), total antioxidant activity (TAA), vitamin C (VC), vitamin E (VE) and retinol (RET) as antioxidative indicators. Their correlation with features of MS was analyzed including their dependency on lipid pattern. RESULTS: SOD, TAA, VE and RET in the PCOS group and PCOS + MS group were lower and MDA higher than in the control group (p < 0.05). SOD, VE and RET were the lowest in PCOS + MS group (p < 0.05). Thus, patients in this group had the highest oxidative stress levels but the lowest antioxidative capacity. SOD and TAA significantly decreased with increase of triglycerides (TG) and LDL-C in the PCOS + MS group (p < 0.05), but without dependency on HDL-C. Stepwise multiple linear regression analysis confirmed the different expression of oxidative stress in the three groups and decrease of SOD from control to PCOS group to PCOS + MS group, being associated with an increase of TG. CONCLUSIONS: MS can accelerate the oxidative stress process in patients with PCOS and decrease the antioxidative capacity. The decreased antioxidant capacity in PCOS with MS is related to increased TG and LDL-C.

Membrane-initiated effects of Serelys® on proliferation and apoptosis of human breast cancer cells.

Herbal extracts used for the alleviation of postmenopausal symptoms might have a lower risk of breast cancer development than hormone therapy. Serelys® is a product composed of purified pollen cytoplasm extracts. Recent experimental data revealed that estrogens might trigger a further proliferative effect on breast cancer cells via the progesterone receptor membrane component-1 (PGRMC1) in addition to the proliferative effect via intracellularly located receptors. MCF-7 and T47D cells were stably transfected with PGRMC1. Different concentrations of the extract alone and in combination with fixed concentrations of estradiol or a growth factor mixture were tested. Proliferation of treated cells was determined by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide (MTT)-test and apoptosis was determined using a Cell Death Detection ELISA kit (CDD). Serelys® was neutral in the cell lines transfected or not transfected with PGRMC1. It was also neutral in combination with estradiol or growth factors in terms of cell proliferation and cell apoptosis. Thus in contrast to hormone therapy Serelys® appears to trigger no further breast cancer risk when applied in the post menopause to women, who do or do not overexpress PGRMC1. Overall Serelys® may be an effective alternative for alleviating postmenopausal symptoms without increasing breast cancer risk.

Effect of Diane-35, alone or in combination with orlistat or metformin in Chinese polycystic ovary syndrome patients.

OBJECTIVE: To evaluate the effect of Diane-35, alone or in combination with orlistat or metformin, on androgen and body fat percentage parameters in Chinese overweight and obese polycystic ovary syndrome (PCOS) patients with insulin resistance. METHODS: A total of 240 PCOS women were randomly allocated to receive Diane-35 alone (D group), Diane-35 plus orlistat (DO group), Diane-35 plus metformin (DM group), or Diane-35 plus orlistat plus metformin (DOM group). Serum TT, DHEA-S, androstenedione, SHBG, FT, FAI, body fat, and body fat percentage were assessed at baseline and after 12 weeks of treatment. RESULTS: Significant changes in serum TT, SHBG, and FAI were observed in all treatment groups compared with baseline. DHEA-S and androstenedione significantly decreased in the DO, DM, and DOM groups after treatment. FT only significantly decreased in the DOM group. Body fat and body fat percentage significantly decreased in the DO and DOM groups. Compared with the D group, DHEA-S significantly decreased in the DO, DM, and DOM groups (F = 4.081, p = 0.008); SHBG significantly increased in the DOM group (F = 3.019, p = 0.031); and FAI significantly decreased in the DO group (χ2 = 12.578, p = 0.006). There were significant differences between groups in body fat percentage (χ2 = 23.590, p < 0.001). Side-effects were less with orlistat than metformin. CONCLUSIONS: Diane-35 in combination with orlistat or metformin is more effective in reducing androgen than Diane-35 alone. Orlistat is more effective in reducing body fat percentage than metformin. In addition, orlistat has mild side-effects and is better tolerated compared with metformin.

High Level of Progesteron Receptor Membrane Component 1 (PGRMC 1) in Tissue of Breast Cancer Patients is Associated with Worse Response to Anthracycline-Based Neoadjuvant Therapy.

PGRMC1 is known to be highly expressed in breast cancer tissue and is associated with chemoresistance in breast cancer cells. However, its role in breast cancer signaling is not fully understood yet. In the present study, the expression status of PGRMC1 and its phosphorylated version (pPGRMC1) in breast cancer tissue and surrounding stroma before and after neoadjuvant therapy was examined to find a possible association to therapy response. Tissue biopsies of 69 breast cancer patients were analyzed by immunohistochemistry for expression levels of PGRMC1 and pPGRMC1. Expression status of PGRMC1 and pPGRMC1 in tumor tissue was compared with expression status of progesterone receptor (PR), estrogen receptor α (ERα), total estrogen receptor ß (ERß), ERß1, ERß2, the proliferation marker Ki-67, and human epidermal growth factor receptor 2 (HER2/neu). Correlations were calculated for expression of PGRMC1 and pPGRMC1 before and after neoadjuvant-therapy. PGRMC1 and pPGRMC1 were highly abundant in every breast cancer tissue sample. Considerably lower signals were detected in surrounding tissue. Further, PGRMC1 and pPGRMC1 abundance was found to correlate with ERß expression. A lower level of pPGRMC1 could be found in post-therapy surgical specimens compared to specimens before treatment. Interestingly, patients with high PGRMC1 tumor levels showed worse response to anthracycline-based therapy as patients with lower PGRMC1 levels. These new findings demonstrate that PGRMC1 might play an important role in progression and therapy resistance of human breast tumors and could offer an interesting target for anticancer therapy.

Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study.

BACKGROUND AND AIM: There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS). METHODS: Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3 months. All patients got LTZ on day 3 for 5 d in combination with Hp-HMG, starting with 75 IU from cycle day 7 and maintained for up to 3 d. The maximum dose was 150 IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events. RESULTS: Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen. CONCLUSIONS: LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.