Adrenal androgens and the menopausal transition

The concept that adrenal androgen production gradually declines with age has changed after analysis of longitudinal data from the Study of Women's Health Across the Nation (SWAN). It is now recognized that 4 adrenal androgens rise during the menopausal transition in most women. Ethnic and individual differences in sex steroids are more apparent in circulating adrenal steroids than in either estradiol or cyclic ovarian steroid hormone profiles, particularly during the early and late perimenopause. Thus, adrenal steroid production may play a larger role in the occurrence of symptoms and the potential for healthier aging than previously recognized.     

Correlation of cervicovaginal fluid volume with serum estradiol levels and total follicular volume during human gonadotropin stimulation

During the normal menstrual cycle the volume of cervicovaginal fluid (CVF), as determined by the patient at home using a simple volumetric aspirating pipette, increases significantly over several days prior to the luteinizing hormone (LH) surge and decreases characteristically shortly after ovulation. The present study was undertaken to test the hypothesis that self-determined measurements of CVF volume would correlate positively with serum estradiol (E₂)levels and with total follicular volume (TFV) in cycles stimulated with exogenous gonadotropins. Consequently, 20 infertility patients, undergoing human menopausal gonadotropin (hMG)-stimulated cycles, were asked to measure daily CVF. Routine serum E ₂ determinations and vaginal follicular ultrasound studies were performed up to and including the day of human chorionic gonadotropin (hCG) administration (designated day 0). The mean daily CVF volume (±SD) increased from 0.1 ± 0.01 ml on day –6 to 0.7 ± 0.40 ml on day — 1 and then decreased to 0.6 ± 0.40 ml on day 0. On day 0, 7 of 20 cycles (35%) demonstrated a decrease in CVF, which ranged from 0.1 to 1.0 ml (mean, 0.42 ml). The mean daily CVF correlated positively (correlation coefficient = r) with the mean daily serum E ₂ (r = 0.89) and with the mean daily TFV (r =0.88). The mean daily correlation of TFV for E ₂ was r =0.98. The correlation between CVF and E ₂ of individuals ranged from r =0.38 to r =0.99 and the correlation between CVF and TFV ranged from r =0.12 to r =1.0, while the individual correlations ofE ₂ to TFV ranged from r =0.60 to r =0.99. These early data suggest that, although mean daily levels of CVF increase positively over time, individual CVF levels are not sensitive enough, alone, to replace the traditional methods of monitoring hMG-stimulated cycles.     

Hypersensitization to human menopausal gonadotropins with anaphylactic shock syndrome during a fifth in vitro fertilization cycle

Conclusion Allergic reactions to therapies with human urinary-derived gonadotropins are of a low incidence. They may, however, have serious consequences as reported in our case study. In our opinion, they are probably related to the presence of copurified urinary proteins. One might hypothesize that highly purified and/or recombinant human gonadotropins will reduce this incidence yet further in the future.     

Evaluation of predictive factors for multiple pregnancies during gonadotropin/IUI treatment

Purpose: Our purpose was to analyze factors for their predictability of multiple pregnancies in patients treated with a combination of human menopausal gonadotropins (hMG) and intrauterine insemination (IUI). Methods: The records of all patients conceiving through treatment with hMG/IUI were reviewed for factors predictive of multiple pregnancy. Results: Ninety-one pregnancies reviewed included 78 singleton (86%), 8 twin (9%), and 5 higher-order pregnancies (5%). The total number of follicles >10 mm was greater in the multiple-pregnancy group and there was a decreased number of postwash sperm in the multiple-pregnancy group. Otherwise there was no significant difference in the factors analyzed. Conclusions: No factor or combination of factors predicts multiple pregnancies to a degree that it would be helpful in managing or counseling patients.     

The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin

The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n?=?155 and n?=?188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2?ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (≥15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p?=?0.025) and 31% versus 49% (p?=?0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p?=?0.074; antagonist protocol: 34% versus 23%, p?=?0.075; overall population: 34% versus 22%, p?=?0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders.     

Exogenous gonadotropin administration affects the glycocalyx of rat endometrial epithelial cells during the period of implantation

Purpose Exogenous gonadotropins which cause superovulation are known to effect endometrial morphology, including the glycocalyx of surface epithelial cells. Certain of the carbohydrates in the glycocalyx of surface epithelial cells may be involved in the attachment and implantation of the blastocyst.Methods The effect of exogenous gonadotropins on specific carbohydrates in the glycocalyx of the rat endometrium around the time of implantation was investigated. Lectin-avidin-biotin-ferritin cytochemistry was used to ascertain which carbohydrates were affected. The lectins soybean agglutinin, fucose binding protein and wheat germ agglutinin were used.Results Statistically significantly less lectin was associated with the apical membrane of surface epithelial cells of animals following hyper stimulation than in noninjected pregnant animals.Conclusions The reduction in the carbohydrates contributes to a reduced receptivity of the endometrium for the blastocyst.     

Correlation between allopregnanolone levels and depressive symptoms during late menopausal transition and early postmenopause

Objectives: This observational, cross-sectional study included 140 women with climacteric symptoms. The aim of the study was to evaluate the correlation between the presence and severity of depressive symptoms and allopregnanolone levels in women during late menopausal transition and early postmenopause.

Methods: The study group was divided into two groups: 45 women in late menopausal transition and 95 early postmenopausal women. We evaluated Kupperman index, Hamilton scale and serum follicle-stimulating hormone, luteinizing hormone, 17β-estradiol, prolactin, total testosterone, dehydroepiandrosterone sulfate and allopregnanolone levels.

Results: We found that serum allopregnanolone concentration was lower in early postmenopausal women compared to women in late menopausal transition; that there was a correlation between serum allopregnanolone levels in early postmenopausal women and time since last menstruation, intensity of climacteric symptoms, and intensity of depression symptoms and that there was a correlation between serum allopregnanolone levels and several depression symptoms presence (shallow sleep and symptoms of the digestive tract in women during late menopause transition; feelings of guilt, sleep disorders and general somatic symptoms in early postmenopausal women).

Conclusion: We concluded that reproductive aging is characterized by a reduction of allopregnanolone circulating levels that correlate to Hamilton depression index in early postmenopause and presence of specific depressive symptoms during late menopausal transition and early postmenopause.     

Sleep during the perimenopause: a SWAN story

Is there evidence for a perimenopausal sleep disorder? We address this question in our presentation of the Study of Women's Health Across the Nation (SWAN) "sleep story," in which we summarize and discuss data addressing sleep quality, objective measures of sleep patterns, and sleep disorders that have been published to date by the SWAN and the ancillary SWAN Sleep Study. We describe what has been learned about sleep during the perimenopause. Analyses exploring racial/ethnic diversity and the role of hot flashes and mood disturbance in sleep-perimenopause associations are described. Implications for clinical practice are considered.     

Safety and efficacy of tibolone and menopausal transition: a randomized,double-blind placebo-controlled trial

Objective: To evaluate the efficacy, safety and tolerability of Tibolone use during the menopausal transition (MT). Methods: Sixty-five healthy women aged 40–55 years (48.5?±?3.5 years) were recruited for a randomized, double-blind controlled trial. Thirty participants were recruited to receive oral Tibolone 2.5?mg/day – Tibolone Group (TG), and 35 participants were assigned to the Placebo Group (PG), which received one capsule of lactose/day. Both groups were treated for 12 consecutive weeks. The Blatt-Kupperman Menopausal Index (KMI) and the Greene Climacteric Scale (GCS) were used. The glycaemic and lipid profiles, biochemical measures of hepatic function and endometrial thickness were measured for safety. A daily registry of complaints related to the treatment was maintained, and anthropometric measures were obtained to assess tolerability. Results: A total of 57 women completed the study. After 12 weeks of Tibolone use, the total score and percentage of the KMI and GCS were significantly decreased compared to baseline, which reflected the efficacy of the treatment of climacteric symptoms. The improvement in blood biochemistry, endometrial atrophy and maintenance of the anthropometrical measures reflected the safety of Tibolone use. The absence of serious side effects demonstrated good tolerability for Tibolone use. Conclusions: The results showed good efficacy, tolerability and safety of Tibolone use during the MT.     

Pasteurella multocida as a rare cause of neonatal meningitis

Pasteurella multocida (P. multocida), a Gram-negative bacillus is a typical commensal in the oropharynx of animals such as dogs and cats. Human diseases caused by P. multocida are rare and include respiratory infections, sepsis and meningitis. P. multocida infections are described predominantly in patients with underlying chronic disorders, in elderly patients or in infants < or = 1 year. We describe the case of a 3-week-old boy with meningitis due to Pasteurella multocida. P. multocida was also identified in oral swab and stool cultures of the pet cat. A direct contact between baby and cat was negated by the parents. The patient recovered without any neurological sequelae.     

Impact of leuprolide acetate on the response to follicular stimulation for in vitro fertilization in patients with normal basal gonadotropin levels

Fifteen women with normal basal gonadotropin levels and adequate responses to conventional gonadotropin stimulation for in vitro fertilization (IVF) were pretreated with leuprolide acetate (LA) beginning in the midluteal phase prior to a repeat IVF attempt. A significantly longer duration of stimulation requiring a significantly higher total dosage of gonadotropins was observed in LA cycles. The number of preovulatory oocytes retrieved and preembryos transferred was significantly higher in LA cycles. Six of 15 women (40%) had cryopreservation of supernumerary preembryos in LA cycles, versus none in non-LA cycles; 22% of preovulatory oocytes aspirated in LA cycles were available for cryopreservation for future transfer. Five pregnancies occurred in the 15 LA cycles. IVF patients with normal basal gonadotropin levels and normal responses to conventional gonadotropin stimulation benefit from LA pretreatment.     

Anti-Helicobacter pylori antibodies in cervical mucus: a new cause of infertility

Objective

The aims of our study were to determine on the one hand a correlation between the presence of anti-Helicobacter pylori (anti-H. pylori) IgG antibodies in serum and cervical mucus of women with idiopathic infertility, and on the other hand the effect of these antibodies on cervical mucus quality, in particular related to the ability of spermatozoa to penetrate it.

Study design

We analysed anti-H. pylori IgG antibodies in the serum and cervical mucus of 67 patients diagnosed with idiopathic infertility using the Quanta Lite H. pylori IgG test. The penetration of normal sperm, in 15 cervical mucus samples positive for anti-H. pylori antibodies and in 15 negative samples, was assessed using the simplified slide test.

Results

A significant positive correlation emerged between anti-H. pylori IgG antibody concentrations in the serum and in the cervical mucus (r = 0.9275; p < 0.00001). In the 15 anti-H. pylori IgG mucus-positive samples the slide test showed abnormal penetration by the spermatozoa.

Conclusions

Our study demonstrated that the presence of anti-H. pylori antibody in the cervical mucus can be involved in female infertility, interfering with sperm progression. Considering the close correlation found between serum and cervical mucus anti-H. pylori antibody titres, measuring serum antibodies could become an additional test, in particular in couples with unexplained infertility.     

Supplementation with human menopausal gonadotropin in the gonadotropin-releasing hormone antagonist cycles of women with high AMH: Pregnancy outcomes and serial hormone levels

ObjectiveTo evaluate the value of using both HMG and recombinant FSH (r-FSH) in the GnRH antagonist protocol for women with high AMH.Materials and methodsThis retrospective, single-center cohort study was conducted from January 2013 to December 2018. Of 277 GnRH antagonist IVF/ICSI cycles in women with anti-Mullerian hormone (AMH) ≥5 μg/L, 170 cycles receiving the combination of r-FSH and HMG (77 with HMG added at the beginning of the GnRH antagonist cycle and 93 with HMG added after GnRH antagonist administration) and 107 cycles receiving r-FSH alone were analyzed. The dynamic hormone profiles and embryonic and clinical outcomes of the patients were evaluated.ResultsWe observed significantly lower serum LH levels in the r-FSH + HMG groups during ovarian stimulation. The serum estradiol and progesterone levels were lower in the r-FSH + HMG groups on the trigger day. Nevertheless, there were no significant differences with respect to the number of oocytes retrieved, maturation, fertilization, blastocyst formation rate or ovarian hyperstimulation syndrome (OHSS). The implantation and live birth rates were increased in the r-FSH + HMG groups compared with the r-FSH alone group, with no statistical significance.ConclusionsHMG for LH supplementation in the GnRH antagonist protocol for patients with high AMH is not significantly superior to r-FSH alone in terms of ovarian response and pregnancy outcome. Nevertheless, HMG supplementation might be appropriate for women with an initially inadequate response to r-FSH or intracycle LH deficiency.     

Inhibin A and B as markers of menopause: a five-year prospective longitudinal study of hormonal changes during the menopausal transition

OBJECTIVES: A more direct and precise hormonal marker of the menopause has been required for some time. The aim of this study was to identify the most accurate marker of the menopause, based on analyses of inhibin A and B, FSH, LH and estradiol (E(2)), among 59 healthy women without hormonal treatment during the perimenopause and early postmenopause. METHODS: Fifty-nine women, aged 46-56 years (mean age 51.2 years), were examined annually for 5 years during the menopausal transition and had venous blood drawn simultaneously for later analyses of the above-mentioned hormones. RESULTS: Inhibin A showed a steady decline from at least 4 years before the final menstrual period (FMP) until 1 year before menopause, whereas inhibin B had a shorter lasting decline from year 3 to year 2 before menopause, concomitant with a rise in FSH and LH. CONCLUSION: The present study confirmed previous observations that inhibin A had a continuous decline starting before the decline of inhibin B, suggesting that an increasing part of the cycle was anovulatory. The fall in inhibin B and the increase in FSH constitute markers of ovarian aging. One year prior to menopause neither inhibin A nor inhibin B could be detected. The disappearance of these peptide hormones is an important predictor of the approaching menopause.     

Increased angiotensin II in ascites during severe ovarian hyperstimulation syndrome: role of early pregnancy and ovarian gonadotropin stimulation

Objective: To investigate the implications of the ovarian renin-angiotensin system (RAS) in the pathophysiology of the ovarian hyperstimulation syndrome (OHSS) in relation to gonadotropin stimulation and early pregnancy.

Design: A controlled clinical study comparing blood and simultaneously sampled peritoneal fluid (PF) from patients with severe OHSS and from controls without OHSS.

Setting: University Hospitals.

Patient(s): Eleven patients with severe DHSS, 8 patients with ascites of other origin, 9 patients with a first-trimester pregnancy, and 15 patients stimulated with gonadotropins for IVF.

Main outcome measure(s): Angiotensin II immunoreactivity was measured in blood and PF and analyzed by high-performance liquid chromatography (HPLC) in ascites from OHSS.

Result(s): Angiotensin II immunoreactivity (pg/mL; mean ± SE) was highest in the ascites from pregnant OHSS (1,669 ± 418), reaching levels 5 times higher than in the plasma (331 ± 61) and 100 times higher than in control ascites (17 ± 6.7). Angiotensin II immunoreactivity was elevated in the PF during early pregnancy (211 ± 68) and after gonadotropin stimulation (244 ± 41) and was higher than in the plasma in both groups. Analysis by HPLC showed that the majority of Ang II immunoreactivity in the ascites of OHSS was because of true Ang II.

Conclusion(s): Severe forms of OHSS, especially those associated with pregnancy, are consistently characterized by huge concentrations of Ang II immunoreactivity in the ascites, proved to be true Ang II by HPLC analysis. This may be due to the synergistic effects of exogenous and endogenous hCG on the ovarian RAS.     

Celiac disease as a rare cause of primary amenorrhea: a case report

BACKGROUND: Primary amenorrhea can be due to abnormal functioning of the hypothalamic-pituitary axis or malformation of müllerian structures. Malnutrition due to chronic malabsorption can alter the axis and can be a cause of primary amenorrhea. CASE: A 20-year-old woman presented to us with primary amenorrhea and failure of development of secondary sexual characteristics. She had significant weight loss in spite of normal intake of diet. On investigation, she had microcytic hypochromic anemia, and her follicle-stimulating hormone and luteinizing hormone levels were low, while the thyroid-stimulating hormone and prolactin levels were normal. Her duodenal biopsy showed villus atrophy, and IgA antiendomysial antibody was positive, suggestive of celiac disease. The patient's condition improved markedly and attained menarche after 6 months of a gluten-free diet. CONCLUSION: Celiac disease should be considered in patients presenting with malnutrition and primary amenorrhea.     

The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation

Objective

Prophylactic salpingo-oophorectomy is recommended to women who carry a BRCA1 or BRCA2 mutation to reduce the risks of breast, ovarian and fallopian tube cancer. We measured the impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual functioning in women with a BRCA mutation.

Methods

Women who underwent prophylactic salpingo-oophorectomy between October 1, 2002 and June 26, 2008 for a known BRCA1 or BRCA2 mutation were invited to participate. Participants completed questionnaires before prophylactic surgery and again one year after surgery. Measures of sexual functioning and menopausal symptoms before and after surgery were compared. Satisfaction with the decision to undergo prophylactic salpingo-oophorectomy was evaluated.

Results

114 women who underwent prophylactic surgery completed questionnaires before and one year after surgery. Subjects who were premenopausal at the time of surgery (n = 75) experienced a significant worsening of vasomotor symptoms (hot flashes, night sweats and sweating) and a decline in sexual functioning (desire, pleasure, discomfort and habit). The increase in vasomotor symptoms and the decline in sexual functioning were mitigated by HRT, but symptoms did not return to pre-surgical levels. HRT decreased vaginal dryness and dyspareunia; however, the decrease in sexual pleasure was not alleviated by HRT. Satisfaction with the decision to undergo prophylactic salpingo-oophorectomy remained high regardless of increased vasomotor symptoms and decreased sexual function.

Conclusions

Women who undergo prophylactic salpingo-oophorectomy prior to menopause experience an increase in vasomotor symptoms and a decrease in sexual functioning. These symptoms are improved by HRT, but not to pre-surgical levels.