A minority of women of childbearing potential are tested for pregnancy before chemoimmunotherapy: an Australian cancer centre experience.

BACKGROUND: Chemotherapy is potentially harmful to a developing foetus, and there are limited data on the foetal impact of chemoimmunotherapy (CIT). Therefore, determining pregnancy status prior to initiation of CIT should be standard of care. AIMS: To determine how many women of childbearing age are tested for pregnancy prior to immunochemotherapy administration. METHODS: A retrospective chart review at a large Australian metropolitan cancer referral centre, including 304 women aged 18-51 years with a diagnosis of cancer receiving outpatient-based CIT between 1 May 2015 and 12 June 2020. We assessed the uptake of pregnancy screening and contraception counselling prior to and during first-line CIT. RESULTS: Only 17.3% of CIT cycles (n = 416) screened patients for pregnancy no more than 90 days prior to administration, and the median time between pregnancy screening and treatment was approximately 3 weeks. One patient with early breast cancer had a spontaneous miscarriage estimated at 3-4 weeks' gestation, and neither the patient nor the treating oncologist was aware of this event. This was also the only patient who had a pregnancy test beyond the first cycle of CIT during their treatment. CONCLUSIONS: Our results highlight a concerningly low rate of pregnancy screening in women of childbearing age receiving CIT. The implication of missing a positive pregnancy test in this group of women could result in foetal complications, accidental miscarriage, potential bleeding risks and avoidable psychosocial stress. This highlights the urgent need for guidelines to mandate pregnancy testing in women of childbearing age receiving CIT and evidence-based implementation tools.

Rates of Menstrual History-Taking and Counseling With Anticancer Treatments Are Low: People Who Menstruate Deserve Gender-Specific Cancer Care.

BACKGROUND: Chemotherapy predisposes people who menstruate to abnormal uterine bleeding that can be life-threatening and may also damage ovaries, resulting in premature menopause. The purpose of this study was to explore the incidence of menstrual history documentation and counseling before, during, and after cancer treatment. PATIENTS AND METHODS: The medical charts of 137 consecutive females (self-reported) aged 18 to 49 years receiving anticancer treatment at a major tertiary metropolitan hospital in Australia between 2017 and 2020 were reviewed. Data collected included primary diagnosis, stage of cancer, treatment(s) received, rates of remission or progression, documentation of involvement of a specialist gynecologist, reproductive history, menstrual disturbances, menstruation counseling or intervention offered, and diagnosis of early ovarian failure. RESULTS: Only 16.1% of patients had their menstrual history documented at the initial consult, and 49.6% had their menstrual history documented at a subsequent consult with their treating oncologist or hematologist. Most (82.4%) patients with a menstrual history documented experienced menstrual disturbance posttreatment, most commonly amenorrhea (48.0%), followed by menopause or menopause symptoms (20.6%), irregular menstrual bleeding (16.7%), menorrhagia (13.7%), dysmenorrhea (3.9%), and iron deficiency from bleeding (2.9%). Menopause/Menopausal symptoms and iron deficiency were more likely to be treated than other disturbances. CONCLUSIONS: Menstruation disturbance is a common side effect of cancer treatment. Menstrual care should be integral to cancer care for people who menstruate, and higher engagement could be achieved through education of medical and allied health staff, information technology systems automating prompts and referral pathways, regular audits to ensure compliance, better alliances between cancer and fertility specialists, and the creation of accessible patient information to promote awareness and facilitate discussion.

Oocyte-Secreted Serum Biomarkers GDF9 and BMP15 in Women with Endometriosis.

Oocyte-secreted growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are critical paracrine regulators of female fertility. Recent studies demonstrated that serum concentrations are associated with the number of oocytes retrieved during IVF, and therefore potential clinical use as biomarkers. However, it is unknown if the presence of endometriosis affects serum GDF9 or BMP15. An exploratory case-control study was prospectively performed on 60 women who underwent laparoscopy between April 2017 and August 2018 at two hospitals. GDF9 and BMP15 were measured by validated immunoassays in pre-operative serum samples. Data were analysed relative to laparoscopic assessment of endometriosis and staging. There were 35 women with confirmed laparoscopic diagnosis of endometriosis and 25 controls with no evidence of endometriosis at laparoscopy. GDF9 was detectable in 40% of controls and 48% of cases. There was no difference in median GDF9 concentrations between controls (20.0 pg/ml, range 20.0-2504 pg/ml) and cases (20.0 pg/ml, range 20.0-2963 pg/ml). BMP15 was detectable in 48% of controls and 58% of cases, with no difference in median concentrations between controls (26.5 pg/ml, range 24.0-1499 pg/ml) and cases (24.0 pg/ml, range 24.0-796 pg/ml). Furthermore, there were no significant differences in the proportion of detectable samples or concentrations of GDF9 or BMP15 with differing severities of endometriosis. In conclusion, serum concentrations of oocyte-secreted factors, GDF9 and BMP15 did not differ between control patients and patients with endometriosis. For clinical application in reproductive medicine, GDF9 and BMP15 serum biomarker quantitation is unlikely to be aberrant in the presence of endometriosis.

Comparison of total and endometrial circulating cell-free DNA in women with and without endometriosis.

RESEARCH QUESTION: Do women with laparoscopically confirmed endometriosis have higher plasma concentrations of circulating cell-free DNA (cirDNA) than those without endometriosis? DESIGN: Prospective study of women aged 18-45 years undergoing benign gynaecological laparoscopy at two tertiary hospitals. Venous blood was collected immediately before surgery, and women were allocated to the endometriosis or control groups based on surgical findings. Total plasma cirDNA and cirDNA integrity were measured by quantitative polymerase chain reaction (qPCR) targeting short (115 bases) and long (247 bases) ALU segments. Endometrial-derived cirDNA was measured by qPCR of bisulfite-treated cirDNA using primers selective for a FAM101A sequence uniquely unmethylated in endometrial tissue. Five cirDNA parameters were compared between the control and endometriosis cohorts: total cirDNA concentration, long-stranded cirDNA concentration, integrity ratio, endometrial cirDNA concentration and endometrial cirDNA proportion. RESULTS: Twenty-eight endometriosis and 15 control samples were included. Women with and without endometriosis had cirDNA concentrations of 2.24 ± 0.89 ng/ml and 2.56 ± 0.92 ng/ml, respectively. Analysis by phenotype of endometriosis revealed a significantly higher endometrial cirDNA concentration in women with superficial disease (n = 10) compared with deep endometriosis (n = 18) (mean difference 0.14 ng/ml; 95% CI 0.15 to 0.26; P = 0.025), but not with controls. CONCLUSIONS: No significant differences were found in any of the cirDNA parameters between women with and without endometriosis. The low statistical power and heterogenous pelvic pathology in the control group render it difficult to determine whether the negative results reflect a true lack of increase in cirDNA in endometriosis.

Translational Physiology of Anti-Müllerian Hormone: Clinical Applications in Female Fertility Preservation and Cancer Treatment.

Background: Whilst the ability of AMH to induce the regression of the Müllerian ducts in the male fetus is well appreciated, AMH has additional biological actions in relation to steroid biosynthesis and ovarian follicle dynamics. An understanding of the physiology of AMH illuminates the potential therapeutic utility of AMH to protect the ovarian reserve during chemotherapy and in the treatment of female malignancies. The translation of the biological actions of AMH into clinical applications is an emerging focus of research, with promising preliminary results. Objective and Rationale: Studies indicate AMH restrains primordial follicle development, thus administration of AMH during chemotherapy may protect the ovarian reserve by preventing the mass activation of primordial follicles. As AMH induces regression of tissues expressing the AMH receptor (AMHRII), administration of AMH may inhibit growth of malignancies expressing AMHR II. This review evaluates the biological actions of AMH in females and appraises human clinical applications. Search Methods: A comprehensive search of the Medline and EMBASE databases seeking articles related to the physiological functions and therapeutic applications of AMH was conducted in July 2021. The search was limited to studies published in English. Outcomes: AMH regulates primordial follicle recruitment and moderates sex steroid production through the inhibition of transcription of enzymes in the steroid biosynthetic pathway, primarily aromatase and 17α-hydroxylase/17,20-lyase. Preliminary data indicates that administration of AMH to mice during chemotherapy conveys a degree of protection to the ovarian reserve. Administration of AMH at the time of ovarian tissue grafting has the potential to restrain uncontrolled primordial follicle growth during revascularization. Numerous studies demonstrate AMH induced regression of AMHR II expressing malignancies. As this action occurs via a different mechanism to traditional chemotherapeutic agents, AMH has the capacity to inhibit proliferation of chemo-resistant ovarian cancer cells and cancer stem cells. Wider Implications: To date, AMH has not been administered to humans. Data identified in this review suggests administration of AMH would be safe and well tolerated. Administration of AMH during chemotherapy may provide a synchronistic benefit to women with an AMHR II expressing malignancy, protecting the ovarian reserve whilst the cancer is treated by dual mechanisms.

The effect of laparoscopic salpingectomy for ectopic pregnancy on ovarian reserve.

BACKGROUND: Salpingectomy may damage ovarian reserve by direct vascular interruption to the ovary or thermal vascular injury from electrosurgery. It is plausible that this risk may increase in the context of salpingectomy conducted for ectopic pregnancy due to the distension of the fallopian tube and vascular changes associated with pregnancy. AIM: To report anti-Müllerian hormone (AMH) concentrations before and after laparoscopic salpingectomy for ectopic pregnancy as an indicator of change in ovarian reserve. MATERIALS AND METHODS: Women aged 18-44 years scheduled for salpingectomy for tubal ectopic pregnancy were prospectively recruited. Serum AMH concentrations were measured immediately prior to surgery, then repeated four months post-operatively. In all cases, salpingectomy was conducted laparoscopically using bipolar electrosurgery and mechanical scissors. A group of women scheduled for uterine curettage for first trimester miscarriage was recruited to ensure any observed change in AMH concentration in the women undergoing salpingectomy was secondary to surgery, rather than an effect of pregnancy. RESULTS: Paired pre- and post-operative serum AMH concentrations were obtained from 32 women with tubal ectopic pregnancy. The mean age of the women was 33.6 ± 4.6 years. There was no significant difference in the median pre- and post-operative AMH concentrations (13.00 pmol/L (range 5-67 pmol/L) vs 15.25 pmol/L (range 3-96 pmol/L), P = 0.575). Median AMH concentrations also remained stable in women experiencing a first trimester miscarriage (10.40 pmol/L (range 3.9-37.8 pmol/L) vs 13.67 pmol/L (range 2.8-30.5 pmol/L), P = 0.185). CONCLUSION: Laparoscopic salpingectomy using electrosurgery and mechanical scissors does not damage ovarian reserve. AMH concentrations do not fluctuate from baseline in the first trimester of pregnancy.

Fertility preservation in breast cancer patients.

Breast cancer is the most commonly diagnosed cancer in women. As long-term survival rates have improved, there has been a concurrent increase in quality of life considerations, of which fertility preservation is of utmost importance. A number of fertility preservation options are available to women diagnosed with breast cancer, including administration of a GnRH agonist during chemotherapy in an attempt to minimize ovarian damage, oocyte or embryo cryopreservation prior to the administration of chemotherapy, in vitro maturation of oocytes or ovarian tissue cryopreservation. The safety of pregnancy after a diagnosis of breast cancer has been confirmed in numerous studies.

The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: a systematic review.

STUDY QUESTION: Can controlled ovarian hyperstimulation (COH) for fertility preservation be effectively conducted in women with breast cancer without worsening their prognosis? SUMMARY ANSWER: COH with co-administration of letrozole suppresses oestradiol levels without significantly impacting oocyte yield or decreasing disease-free survival rates. WHAT IS KNOWN ALREADY: Oestradiol has the capacity to stimulate the proliferation of breast cancer cells. COH can cause oestradiol levels to rise by an order of magnitude above physiological levels. Concern exists regarding the effect of supra-physiological oestradiol levels in women with a recent diagnosis of breast cancer. STUDY DESIGN, SIZE, DURATION: A systematic review of the literature was performed using MEDLINE (PubMed database), EMBASE and the Cochrane Library. The search was restricted to articles written in English. No restrictions regarding the date of publication were applied. Safety was assessed in terms of relapse rates and cancer-related mortality rates. Peak oestradiol concentrations were recorded for different stimulation protocols. Efficacy was measured in terms of the total number of oocytes collected and proportion of mature oocytes. The primary outcome was mortality/recurrence in premenopausal women with Stage I-IIIB breast cancer who underwent COH in the immediate post-operative period, prior to chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: This is a systematic review of randomized control trials (RCTs), case control and cohort studies reporting on the primary outcome of mortality/recurrence after COH in women with early breast cancer, or secondary outcomes of oocyte yield and peak oestrogen concentration. Owing to the small number of RCTs available, other study types were included. The last electronic search was run in April 2016. Two prospective non-randomized studies reported relapse and breast cancer-related mortality rates in 397 women with breast cancer, of whom 149 underwent COH. Twelve studies reported the peak oestradiol concentrations of 882 women undergoing COH with letrozole co-administration. Four studies compared the oocyte yield of 248 women who underwent COH plus letrozole with 254 women who underwent standard COH. Two studies compared peak oestradiol concentrations and oocyte yield in 61 women who underwent COH with tamoxifen co-administration and 49 women who underwent COH without tamoxifen. One study compared letrozole and tamoxifen co-administration, and another study compared the co-administration of letrozole and anastrozole. MAIN RESULTS AND THE ROLE OF CHANCE: The search identified 1002 records of which 15 were included in the final analysis. There was no evidence of a decline in relapse-free survival rates in the two studies of women with breast cancer who received COH with letrozole co-administration compared with women who did not undergo fertility preservation procedures. The largest of these studies reported recurrences in 6/120 (5.0%) women who received COH plus letrozole compared with 12/217 (5.5%) women who did not undergo COH (mean follow-up 5.0 versus 6.9 years; hazard ratio for recurrence 0.77, 95%CI 0.28-2.13). Conclusions regarding women with breast cancer who received tamoxifen during COH could not be made due to insufficient data. Peak oestradiol concentrations (338-829 pg/ml) were suppressed by letrozole when commenced on Days 2-3, with no decrease in oocyte yield. Tamoxifen does not suppress oestradiol concentrations, but may convey protection via its inhibitory action on the oestrogen receptor. LIMITATIONS, REASONS FOR CAUTION: Any statements regarding the safety of COH in women with breast cancer are based on a limited number of observational studies. High quality evidence is unlikely to become available for ethical and practical reasons. Whilst available data do not indicate a decline in disease-free survival, a small effect cannot be excluded. Breast cancers are heterogeneous in their genetic profile and receptor status, making the results of studies difficult to generalize to individual cases. The implication of alterations in other hormone levels such as androgens, progestins or vascular endothelial growth factor secondary to COH in women with breast cancer has not been quantified. WIDER IMPLICATIONS OF THE FINDINGS: The co-administration of 5 mg of letrozole daily commencing on Day 2 and continuing throughout COH is recommended as it reduces peak oestradiol concentrations without significantly decreasing oocyte yield. The use of a GnRH agonist trigger is beneficial as oestradiol concentrations rapidly decrease post-administration and rates of ovarian hyperstimulation are lower than with an hCG trigger, without a corresponding reduction in clinical pregnancy or live birth rates in cryopreservation cycles. The protective effect of tamoxifen has not been evaluated although theoretically may be of benefit due to its action on the oestrogen receptor. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: None.

Clinical case presentation: life threatening Group A sepsis secondary to HyCoSy.

Hysterosalpingo contrast sonography (HyCoSy) is a commonly performed procedure in the investigation of infertility. Infection is an uncommon complication of this procedure. Should it occur, it is generally mild and amenable to outpatient treatment with oral antibiotics. We present a case of an immunosuppressed woman who underwent HyCoSy for investigation of secondary infertility and developed life-threatening sepsis with Group A streptococcus.