Amber R. Cooper

The time is now for a new approach to primary ovarian insufficiency

OBJECTIVE To articulate the need for a new approach to primary ovarian insufficiency. The condition, also known as premature menopause or premature ovarian failure, is defined by the presence of menopausal-level serum gonadotropins in association with irregular menses in adolescent girls or women younger than 40 years. It can be iatrogenic as related to cancer therapy or may arise spontaneously, either alone or as part of a host of ultrarare syndromes. In a large percentage of spontaneous cases no pathogenic mechanism can be identified. DESIGN Literature review and consensus building at a multidisciplinary scientific workshop. CONCLUSION(S) There are major gaps in knowledge regarding the etiologic mechanisms, psychosocial effects, natural history, and medical and psychosocial management of primary ovarian insufficiency. An international research consortium and disease registry formed under the guidance of an umbrella organization would provide a pathway to comprehensively increase basic and clinical knowledge about the condition. Such a consortium and patient registry also would provide clinical samples and clinical data with a goal toward defining the specific pathogenic mechanisms. An international collaborative approach that combines the structure of a patient registry with the principles of integrative care and community-based participatory research is needed to advance the field of primary ovarian insufficiency.

Maternal tobacco use and its preimplantation effects on fertility: more reasons to stop smoking.

There are numerous health concerns regarding tobacco smoke. Yet, only recently have researchers extensively explored the association between tobacco smoke and a womans inability to conceive. Whether exposure occurs in utero, during pregnancy, or throughout the reproductive years, it can affect all facets of fertility and lead to diminished ovarian function and earlier menopause. This review analyzes the literature concerning the delay or absence of conception in some women exposed to cigarette smoke and provides a detailed examination of the potential reproductive targets of the mutagenic and toxic components of tobacco. A negative influence on ovarian steroidogenesis and gametogenesis, oocyte maturity, ovulation, oocyte cumulus complex pick-up, gamete and embryo transport by the oviduct, fertilization, and implantation could all play a role. Assisted reproductive technology, or more specifically, in vitro fertilization, has allowed us to more thoroughly analyze successful pregnancy cycles and the negative consequences of smoking. Objective measurements of tobacco compounds and their metabolites in follicular fluid correlate with subjective measures of ovarian, gamete, and embryo quality in smokers and in those exposed to passive smoke. Regardless, there is an abundance of literature accumulating and more than enough reasons to tell patients to stop smoking.

Persistent Organic Pollutants and Early Menopause in U.S. Women

Objective Endocrine-disrupting chemicals (EDCs) adversely affect human health. Our objective was to determine the association of EDC exposure with earlier age of menopause. Methods Cross-sectional survey using National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2008 (n = 31,575 females). Eligible participants included: menopausal women >30 years of age; not currently pregnant, breastfeeding, using hormonal contraception; no history of bilateral oophorectomy or hysterectomy. Exposures, defined by serum lipid and urine creatinine-adjusted measures of EDCs, data were analyzed: > 90th percentile of the EDC distribution among all women, log-transformed EDC level, and decile of EDC level. Multi linear regression models considered complex survey design characteristics and adjusted for age, race/ethnicity, smoking, body mass index. EDCs were stratified into long (>1 year), short, and unknown half-lives; principle analyses were performed on those with long half-lives as well as phthalates, known reproductive toxicants. Secondary analysis determined whether the odds of being menopausal increased with EDC exposure among women aged 45–55 years. Findings This analysis examined 111 EDCs and focused on known reproductive toxicants or chemicals with half-lives >1 year. Women with high levels of β-hexachlorocyclohexane, mirex, p,p’-DDE, 1,2,3,4,6,7,8-heptachlorodibenzofuran, mono-(2-ethyl-5-hydroxyhexyl) and mono-(2-ethyl-5-oxohexyl) phthalate, polychlorinated biphenyl congeners −70, −99, −105, −118, −138, −153, −156, −170, and −183 had mean ages of menopause 1.9 to 3.8 years earlier than women with lower levels of these chemicals. EDC-exposed women were up to 6 times more likely to be menopausal than non-exposed women. Conclusions This study of a representative sample of US women documents an association between EDCs and earlier age at menopause. We identified 15 EDCs that warrant closer evaluation because of their persistence and potential detrimental effects on ovarian function. Earlier menopause can alter the quantity and quality of a woman’s life and has profound implications for fertility, human reproduction, and our global society.

Sperm banking for fertility preservation: a 20-year experience.

OBJECTIVE Sperm banking is an effective method to preserve fertility, but is not universally offered to males facing gonadotoxic treatment in the United States. We compared the disposition and semen parameters of cryopreserved sperm from individuals referred for sperm banking secondary to a cancer diagnosis to those of sperm from men banking for infertility reasons. STUDY DESIGN We performed a retrospective cohort study that reviewed 1118 records from males who presented to bank sperm at Washington University between 1991 and 2010. We collected and analyzed demographics, semen parameters, and disposition of banked sperm. RESULTS Four hundred and twenty-three men with cancer and 348 banking for infertility reasons attempted sperm cryopreservation in our unit during the specified time period. The most prevalent cancers in our cohort were testicular (32%), lymphoma (25%), and leukemia (11%). Patients with leukemia had the lowest pre-thaw counts and motility. Most cancer patients (57%) who banked elected to use, transfer to another facility, or keep their specimens in storage. The remaining samples were discarded electively (34%) or following death (8%). Overall semen parameters were similar between the cancer and infertility groups, but demographics, ability to bank a sample, azoospermia rates, length of storage, current banking status, and use of banked sperm differed significantly between the two groups. CONCLUSIONS The majority of cancer patients who banked survived their cancer and chose to continue storage of banked samples. Cancer patients were more likely than infertility patients to use or continue storage of banked samples. Our study provides evidence that sperm banking is a utilized modality of fertility preservation in patients with a myriad of cancer diagnoses and should be offered to all men facing gonadotoxic therapies. Further work is needed to determine where disparities in access to sperm banking exist to improve the potential for future fertility in these males.

Novel use of a tracheobronchial stent in a patient with uterine didelphys and obstructed hemivagina

OBJECTIVE To describe a novel use for a tracheobronchial stent to maintain patency after vaginal septum excision in a patient with an obstructed hemivagina and uterine didelphys. DESIGN Description of a novel technique. SETTING University-affiliated childrens hospital. PATIENT(S) One patient with an obstructed hemivagina and uterine didelphys who presented with hematometria and hematocolpos. INTERVENTION(S) To maintain patency and decrease stenosis risk after vaginal septum excision, a coated tracheobronchial stent was deployed and left in place for 6 weeks. MAIN OUTCOME MEASURE(S) To evaluate ease of stent placement and removal, reepithelialization and patency of the neovagina, and postoperative assessment of pain and recurrent obstruction. RESULT(S) The tracheobronchial stent was easily positioned and deployed with vaginoscopic guidance. Six weeks later it was removed without any tissue ingrowth or granulation tissue noted. The vaginal walls were nicely epithelialized. Twelve months postoperatively, the patient remained pain free with regular cycles and no evidence of obstruction or abnormality on ultrasound. CONCLUSION(S) Use of a coated tracheobronchial stent to maintain patency after septum excision in a patient with an obstructed hemivagina presents a safe, easy, and effective option to diminish stenosis risk and avoid infectious complications or hysterectomy.

Preimplantation Genetic Testing: Indications and Controversies

In the last two decades, the use of preimplantation genetic testing has increased dramatically. This testing is used for identifying singlegene disorders, chromosomal abnormalities, mitochondrial disorders, gender selection in non-mendelian disorders with unequal gender distribution, aneuploidy screening, and other preconceptually identified genetic abnormalities in prospective parents. Genetic testing strategies and diagnostic accuracy continues to improve, but not without risks or controversies. In this review the authors discuss the techniques and clinical application of preimplantation genetic diagnosis, and the debate surrounding its associated uncertainty and expanded use.

Variability in the practice of fertility preservation for patients with cancer

Fertility is important to women and men with cancer. While options for fertility preservation (FP) are available, knowledge regarding the medical application of FP is lacking. Therefore we examined FP practices for cancer patients among reproductive endocrinologists (REs). A 36 item survey was sent to board-certified REs. 98% of respondents reported counseling women with cancer about FP options. Oocyte and embryo cryopreservation were universally offered by these providers, but variability was noted in reported management of these cases—particularly for women with breast cancer. 86% of the respondents reported using letrozole during controlled ovarian stimulation (COS) in patients with estrogen receptor positive (ER+) breast cancer to minimize patient exposure to estrogen. 49% of respondents who reported using letrozole in COS for patients with ER+ breast cancer reported that they would also use letrozole in COS for women with ER negative breast cancer. Variability was also noted in the management of FP for men with cancer. 83% of participants reported counseling men about sperm banking with 22% recommending against banking for men previously exposed to chemotherapy. Overall, 79% of respondents reported knowledge of American Society for Clinical Oncology FP guidelines—knowledge that was associated with providers offering gonadal tissue cryopreservation (RR 1.82, 95% CI 1.14–2.90). These findings demonstrate that RE management of FP in cancer patients varies. Although some variability may be dictated by local resources, standardization of FP practices and communication with treating oncologists may help ensure consistent recommendations and outcomes for patients seeking FP.

Sperm Recovery and IVF after Testicular Sperm Extraction (TESE): Effect of Male Diagnosis and Use of Off-Site Surgical Centers on Sperm Recovery and IVF

Objective Determine whether testicular sperm extractions and pregnancy outcomes are influenced by male and female infertility diagnoses, location of surgical center and time to cryopreservation. Patients One hundred and thirty men undergoing testicular sperm extraction and 76 couples undergoing 123 in vitro fertilization cycles with testicular sperm. Outcome Measures Successful sperm recovery defined as 1–2 sperm/0.5 mL by diagnosis including obstructive azoospermia (n = 60), non-obstructive azoospermia (n = 39), cancer (n = 14), paralysis (n = 7) and other (n = 10). Obstructive azoospermia was analyzed as congenital absence of the vas deferens (n = 22), vasectomy or failed vasectomy reversal (n = 37) and “other”(n = 1). Sperm recovery was also evaluated by surgical site including infertility clinic (n = 54), hospital operating room (n = 67) and physician’s office (n = 11). Treatment cycles were evaluated for number of oocytes, fertilization, embryo quality, implantation rate and clinical/ongoing pregnancies as related to male diagnosis, female diagnosis, and use of fresh or cryopreserved testicular sperm. Results Testicular sperm recovery from azoospermic males with all diagnoses was high (70 to 100%) except non-obstructive azoospermia (31%) and was not influenced by distance from surgical center to laboratory. Following in vitro fertilization, rate of fertilization was significantly lower with non-obstructive azoospermia (43%, p = <0.0001) compared to other male diagnoses (66%, p = <0.0001, 59% p = 0.015). No differences were noted in clinical pregnancy rate by male diagnosis; however, the delivery rate per cycle was significantly higher with obstructive azoospermia (38% p = 0.0371) compared to diagnoses of cancer, paralysis or other (16.7%). Women diagnosed with diminished ovarian reserve had a reduced clinical pregnancy rate (7.4% p = 0.007) compared to those with other diagnoses (44%). Conclusion Testicular sperm extraction is a safe and effective option regardless of the etiology of the azoospermia. The type of surgical center and/or its distance from the laboratory was not related to success. Men with non-obstructive azoospermia have a lower chance of successful sperm retrieval and fertilization.

Sex-related growth differences are present but not enhanced in in vitro fertilization pregnancies

OBJECTIVE To determine whether IVF modifies the effect of fetal sex on growth. DESIGN Retrospective cohort study. SETTING Tertiary care center and related facilities. PATIENT(S) Singleton live births without fetal/maternal comorbidities from fertile women who conceived without the use of assisted reproductive technologies and infertile women who conceived with IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The primary outcome was birth weight (BW). Secondary outcomes were fetal crown-rump length (CRL) in the first trimester, biparietal diameter (BPD), and estimated fetal weight (EFW) in the second trimester. RESULT(S) There were no differences in baseline characteristics between women carrying male fetuses and those carrying female fetuses in either mode of conception. In unadjusted analyses, the male-female differentials in fetal BPD and BW were more pronounced in the IVF cohort than in the unassisted cohort. In multivariable regression analysis, male BPD exceeded female BPD by 0.12 cm, male EFW exceeded female EFW by 12 g, and male BW exceeded female BW by 172 g. IVF did not have a significant effect on BPD but was associated with a 52 g increase in EFW in the midgestation. IVF was associated with an 81-g reduction in BW. IVF did not modify the magnitude of size differences between the sexes in the midgestation or at birth. CONCLUSION(S) Comparable sex-dependent differential growth occurs in unassisted and IVF pregnancies.

Obesity and Ovarian Aging (Diminished Ovarian Reserve and Menopause)

Ovarian aging ultimately results in the cessation of reproductive function and is thought to occur as a result of oocyte depletion. The associated hormonal changes are well defined, and the serum measurements of several of these hormones have been utilized to predict ovarian reserve in women presenting with infertility. Obesity is associated with subfertility and may contribute to pathologic ovarian aging, although a mechanism has yet to be defined. The evaluation of obese women presenting with infertility is complicated by the effect of obesity on markers of ovarian reserve. Additional investigation into the relationship between obesity and ovarian aging is needed to further clarify the role of increased adiposity on infertility, improve the success of assisted reproductive technologies in this population, and better counsel these patients.