Immediate Breast Reconstruction After Mastectomy for Cancer Among US Military Health System Beneficiaries.

BACKGROUND: In the Military Health System (MHS), women with breast cancer may undergo surgical treatment in military hospitals (direct care) or in the civilian setting via the insurance benefit (private sector care). We conducted this study to determine immediate breast reconstruction rates among women undergoing mastectomy for cancer in the MHS by setting of care. METHODS: Using the linked Department of Defense's Central Cancer Registry and MHS Data Repository, the Department of Defense's medical claims database, we identified adult women who underwent mastectomy for breast cancer from 1998 to 2014. Patients were then subgrouped by setting of care (direct vs private sector care). The primary outcome was the rate and type of immediate breast reconstruction. Regression models were constructed to determine factors associated with receipt of immediate breast reconstruction. RESULTS: The final sample included 3251 women who underwent mastectomy for cancer in the direct (67.0%) or private sector care (32.6%) settings. The overall rate of immediate breast reconstruction was 29.9% with an upward trend noted throughout the study (P < 0.001). Overall, implant-based reconstruction (81.4%) was more common than tissue-based reconstruction (18.6%). Compared with direct care, the immediate breast reconstruction rate was significantly higher in the private sector care setting (49.3% vs 20.5%, P < 0.001) despite accounting for differences in clinical characteristics (adjusted odds ratio = 4.51, 95% confidence interval [3.72-5.46]). CONCLUSIONS: Immediate breast reconstruction in the direct care setting lags that in the civilian community during the study time period. Further research is needed to ascertain current immediate reconstruction rates and understand factors contributing to any differences in rates between care settings.

Racial comparisons in treatment of rectal adenocarcinoma and survival in the military health system.

BACKGROUND: Racial disparities in treatment and outcomes of rectal cancer have been attributed to patients' differential access to care. We aimed to study treatment and outcomes of rectal cancer in the equal access Military Health System (MHS) to better understand potential racial disparities. METHODS: We accessed the MilCanEpi database to study a cohort of patients aged 18 and older who were diagnosed with rectal adenocarcinoma between 1998 and 2014. Receipt of guideline recommended treatment per tumor stage, cancer recurrence, and all-cause death were compared between non-Hispanic White and Black patients using multivariable regression models with associations expressed as odds (AORs) or hazard ratios (AHRs) and their 95% confidence intervals (CIs). RESULTS: The study included 171 Black and 845 White patients with rectal adenocarcinoma. Overall, there were no differences in receipt of guideline concordant treatment (AOR = 0.76, 95% CI = 0.45 to 1.29), recurrence (AHR = 1.34, 95% CI = 0.85 to 2.12), or survival (AHR = 1.08, 95% CI = 0.77 to 1.54) for Black patients compared with White patients. However, Black patients younger than 50 years of age at diagnosis (AOR = 0.34, 95% CI = 0.13 to 0.90) or with stage III or IV tumors (AOR = 0.28, 95% CI = 0.12 to 0.64) were less likely to receive guideline recommended treatment than White patients in stratified analysis. CONCLUSIONS: In the equal access MHS, although there were no overall racial disparities in rectal cancer treatment or clinical outcomes between Black and White patients, disparities among those with early-onset or late-stage rectal cancers were noted. This suggests that factors other than access to care may play a role in the observed disparities and warrants further research.

Racial-Ethnic Comparison of Treatment for Papillary Thyroid Cancer in the Military Health System.

PURPOSE: We aimed to compare Asian or Pacific Islander, Black, Hispanic, and non-Hispanic White patients in treatment for papillary thyroid cancer (PTC) in the equal access Military Health System to better understand racial-ethnic cancer health disparities observed in the United States. METHODS: We used the MilCanEpi database to identify a cohort of men and women aged 18 or older who were diagnosed with PTC between 1998 and 2014. Low- or high-risk status was assigned using tumor size and lymph node involvement. Treatment with surgery (e.g., thyroidectomy) overall and treatment by risk status [active surveillance (low-risk) or adjuvant radioactive iodine (RAI) (high-risk)] was compared between racial-ethnic groups using multivariable logistic regression and expressed as adjusted odds ratios (AOR) with 95% confidence intervals (CIs). RESULTS: The study included 598 Asian, 553 Black, 340 Hispanic, and 2958 non-Hispanic White patients with PTC. Asian (AOR = 1.21, 95% CI 0.98, 1.49), Black (AOR = 1.07, 95% CI 0.87, 1.32), and Hispanic (AOR = 0.92, 95% CI 0.71, 1.19) patients were as likely as White patients to receive surgery. By risk status, there were no significant racial-ethnic differences in receipt of active surveillance or thyroidectomy for low-risk PTC or in thyroidectomy or total thyroidectomy with adjuvant RAI for high-risk PTC. CONCLUSIONS: In the Military Health System, where patients have equal access to care, there were no overall racial-ethnic differences in surgical treatment for PTC. As American Thyroid Association guidelines evolve to include more conservative treatment, further research is warranted to understand potential disparities in active surveillance and surgical management in U.S. healthcare settings.

Survival Among Patients With Multiple Myeloma in the United States Military Health System Compared to the Surveillance, Epidemiology, and End Results (SEER) Program.

BACKGROUND: Access to health care is an important factor affecting survival of patients with multiple myeloma (MM) in the U.S. general population. The U.S. Military Health System (MHS) provides universal health care to beneficiaries and has been associated with improved survival across multiple malignancies. In this study, we compared survival of MHS beneficiaries with MM with MM patients from the U.S. general population. MATERIALS AND METHODS: The Department of Defense's Automated Central Tumor Registry (ACTUR) and the Surveillance, Epidemiology and End Results (SEER) databases were used to extract data for MM patients from MHS and the U.S. general population, respectively. Patients had histologically confirmed MM between 1987 and 2013 and were followed through 2015 for overall survival. Two SEER patients were matched to each ACTUR patient by age group, sex, race, and diagnosis year group. Five and 10-year survival was compared between ACTUR and SEER patients to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) with adjustment for potential confounders. RESULTS: Median survival of the ACTUR patients was 47.1 months (95% CI: 43.9-50.4) compared to 33.0 months (95% CI, 32.0-35.0) of the SEER patients. Five and 10-year death rates were significantly lower for ACTUR patients than the SEER patients with an adjusted HR of 0.74 (95% CI, 0.68-0.81) and 0.79 (95% CI, 0.74-0.85), respectively. The survival advantage of ACTUR patients was preserved when stratified by age, sex, race, and diagnosis year. CONCLUSION: MHS beneficiaries with MM had improved overall survival compared to MM patients from the U.S. general population.

Treatment of pancreatic adenocarcinoma in relation to survival in the U.S. Military Health System.

BACKGROUND: Pancreatic cancer has a high case fatality and relatively short survival after diagnosis. Treatment is paramount to improving survival, but studies on the effects of standard treatment by surgery or chemotherapy on survival in U.S. healthcare settings is limited. Further, variability in access to care may impact treatment and outcomes for patients. We aimed to assess the relationship between standard treatment(s) and survival of pancreatic adenocarcinoma in a population with access to comprehensive healthcare. METHODS: We used the Military Cancer Epidemiology (MilCanEpi) database, which includes data from the Department of Defense cancer registry and medical encounter data from the Military Health System (MHS), to study a cohort of 1408 men and women who were diagnosed with pancreatic adenocarcinoma between 1998 and 2014. Treatment with surgery or chemotherapy in relation to overall survival was examined in multivariable time-dependent Cox regression models. RESULTS: Overall, 75 % of 441 patients with early-stage and 51 % of 967 patients with late-stage pancreatic adenocarcinoma received treatment. In early-stage disease, surgery alone or surgery with chemotherapy were both associated with statistically significant 52 % reduced risks of death, but chemotherapy alone was not. In late-stage disease, surgery alone, chemotherapy alone, or both surgery and chemotherapy significantly reduced the risk of death by 42 %, 25 %, and 52 %, respectively. CONCLUSIONS: Our findings from the MHS demonstrate improved survival after treatment with surgery or surgery with chemotherapy for early- or late-stage pancreatic cancer and after chemotherapy for late-stage pancreatic cancer. In the era of immunotherapy and personalized medicine, further research on treatment and survival of pancreatic cancer in observational settings is needed.

Characteristics Associated With Survival in Surgically Nonresected Pancreatic Adenocarcinoma in the Military Health System.

OBJECTIVES: Pancreatic cancer is often diagnosed at advanced stages with high-case fatality. Many tumors are not surgically resectable. We aimed to identify features associated with survival in patients with surgically nonresected pancreatic cancer in the Military Health System. METHODS: We used the Military Cancer Epidemiology database to identify the Department of Defense beneficiaries aged 18 and older diagnosed with a primary pancreatic adenocarcinoma between January 1998 and December 2014 who did not receive oncologic surgery as treatment. We used Cox Proportional Hazard regression with stepwise procedures to select the sociodemographic and clinical characteristics related to 2-year overall survival, expressed as adjusted hazard ratios (aHR) and 95% CIs. RESULTS: Among 1148 patients with surgically nonresected pancreatic cancer, sex, race-ethnicity, marital status, and socioeconomic indicators were not selected in association with survival. A higher comorbidity count (aHR 1.30, 95% CI: 1.06-1.59 for 5 vs. 0), jaundice at diagnosis (aHR 1.57, 95% CI: 1.33-1.85 vs. no), tumor grade G3 or G4 (aHR 1.32, 95% CI: 1.05-1.67 vs. G1/G2), tumor location in pancreas tail (aHR 1.49, 95% CI: 1.22-1.83 vs. head) or body (aHR 1.30, 95% CI: 1.04-1.62 vs. head), and metastases were associated with survival. Patients receiving chemotherapy (aHR 0.66, 95% CI: 0.57-0.76) had better survival compared with no treatment. CONCLUSIONS: In a comprehensive health system, sociodemographic characteristics were not related to survival in surgically nonresected pancreatic cancer. This implicates access to care in reducing survival disparities in advanced pancreatic cancer and emphasizes the importance of treating patients based on clinical features.

The utility of all-freeze IVF cycles depends on the composition of study populations.

BACKGROUND: Because often introduced without proper validation studies, so-called "add-ons" to IVF have adversely affected in vitro fertilization (IVF) outcomes worldwide. All-freeze cycles (embryo banking, EB) with subsequently deferred thaw cycles are such an "add-on" and, because of greatly diverging reported outcomes, have become increasingly controversial. Based on "modeling" with selected patient populations, we in this study investigated whether reported outcome discrepancies may be the consequence of biased patient selection. RESULTS: In four distinct retrospective case control studies, we modeled in four cohort pairings how cryopreservation with subsequent thaw cycles affects outcomes differently in good-, average- and poor-prognosis patients: (i) 127 fresh vs. 193 frozen donor-recipient cycles to model best-prognosis patients; (ii) 741 autologous fresh non-donor IVF cycles vs. 217 autologous frozen non-donor IVF cycles to model average prognosis patients; (iii) 143 favorably selected autologous non-donor IVF cycles vs. the same 217 frozen autologous cycles non-donor to monitor good- vs. average-prognosis patients; and (iv) 598 average and poor-prognosis autologous non-donor cycles vs. the same 217 frozen autologous non-donor cycles to model poor vs. average prognosis patients. In best-prognosis patients, EB marginally improved IVF outcomes. In unselected patients, EB had no effects. In poor-prognosis patients, EB adversely affected IVF outcomes. Unexpectedly, the study also discovered independent-of-age-associated chromosomal abnormalities, a previously unreported effect of recipient age on miscarriage risk in donor-egg recipients. CONCLUSIONS: In poor-prognosis patients, EB cycles should be considered contraindicated. In intermediate-prognosis patients EB does not appear to change outcomes, not warranting additional cost and time delays. Therefore, only good-prognosis patients are candidates for EB, though they will experience only marginal benefits that may not be cost-effective.

MilCanEpi: Increased Capability for Cancer Care Research in the Department of Defense.

The Military Health System (MHS) of the US Department of Defense (DoD) provides comprehensive medical care to over nine million beneficiaries, including active-duty members, reservists, activated National Guard, military retirees, and their family members. The MHS generates an extensive database containing administrative claims and medical encounter data, while the DoD also maintains a cancer registry that collects information about the occurrence of cancer among its beneficiaries who receive care at military treatment facilities. Collating data from the two sources diminishes the limitations of using registry or medical claims data alone for cancer research and extends their usage. To facilitate cancer research using the unique military health resources, a computer interface linking the two databases has been developed, called Military Cancer Epidemiology, or MilCanEpi. The intent of this article is to provide an overview of the MilCanEpi data system, describing its components, structure, potential uses, and limitations.

Changing clinical significance of oocyte maturity grades with advancing female age advances precision medicine in IVF.

In current IVF practice, metaphase-2 (M2) oocytes are considered most efficient in producing good quality embryos. Maximizing their number at all ages is standard clinical practice, while immature germinal vesicle (GV) oocytes are mostly automatically discarded. We present preliminary evidence that oocyte maturity grades with advancing age significantly change in their abilities to produce good quality embryos, with M2 oocytes significantly declining, GV oocytes improving, and M1 oocytes staying the same. These data contradict the over-40-year-old dogma that oocyte grades functionally do not change with advancing age, supporting potential changes to current IVF practice: (1) Stimulation protocols and timing of oocyte retrieval can be adjusted to a patient's age and ovarian function. (2) In older and younger women with prematurely aging ovaries, GV oocytes may no longer be automatically discarded. (3) In some infertile women, rescue in vitro maturation of immature oocytes may delay the need for third-party egg donation.

Nondisparate Survival of Non-Hispanic Black Women With Breast Cancer Despite Less Favorable Pathology: Effect of Access to and Provision of Care Within a Military Health Care System.

Introduction: Breast cancer mortality rates are 40% higher in non-Hispanic Blacks (NHBs) than in non-Hispanic White (NHWs) in the United States. All women treated within the Murtha Cancer Center at Walter Reed National Military Medical Center (MCC/WRNMMC) have health insurance and are provided multidisciplinary health care. Pathological factors and outcomes of NHBs and NHWs treated within the MCC/WRNMMC were evaluated to determine whether equal-access health care reduces disparate phenotypes and survival between the racial groups. Methods: Between 2001 and 2018, 368 NHB and 819 NHW women were diagnosed with breast cancer at MCC/WRNMMC. Differences between NHBs and NHWs in epidemiological and pathological characteristics were evaluated. Overall and breast cancer-specific 5- and 10-year survival rates were compared between races. Results: Compared with NHWs, NHBs were significantly more likely to have a body mass index ≥30 kg/m2, to be unmarried, to have tumors of higher grade, later stage, with lymph node metastases, and to be hormone receptor negative (HR-)/human epidermal growth factor receptor 2 positive (HER2+) or triple negative. After adjustment for demographic factors, NHBs remained significantly more likely to have tumors diagnosed at a higher grade and later stage, and to be HR-/HER2+ or triple negative. Neither 5- nor 10-year overall or breast cancer-specific survival differed significantly between the racial groups after adjusting for demographic and pathological variables. Discussion: Despite having tumors with less favorable pathological characteristics, overall and disease-free survival disparities were not observed for NHBs treated at MCC/WRNMMC. These data suggest that survival disparities of NHBs with breast cancer can be diminished with provision of quality care.

Reconsidering the Polycystic Ovary Syndrome (PCOS).

Though likely the most common clinical diagnosis in reproductive medicine, the Polycystic Ovary Syndrome (PCOS) is still only poorly understood. Based on previously published research, and here newly presented supportive evidence, we propose to replace the four current phenotypes of PCOS with only two entities-a hyperandrogenic phenotype (H-PCOS) including current phenotypes A, B, and C, and a hyper-/hypoandrogenic phenotype (HH-PCOS), representing the current phenotype D under the Rotterdam criteria. Reclassifying PCOS in this way likely establishes two distinct genomic entities, H-PCOS, primarily characterized by metabolic abnormalities (i.e., metabolic syndrome) and a hyperandrogenic with advancing age becoming a hypoandrogenic phenotype (HH-PCOS), in approximately 85% characterized by a hyperactive immune system mostly due to autoimmunity and inflammation. We furthermore suggest that because of hypoandrogenism usually developing after age 35, HH-PCOS at that age becomes relatively treatment resistant to in vitro fertilization (IVF) and offer in a case-controlled study evidence that androgen supplementation overcomes this resistance. In view of highly distinct clinical presentations of H-PCOS and HH-PCOS, polygenic risk scores should be able to differentiate between these 2 PCOS phenotypes. At least one clustering analysis in the literature is supportive of this concept.

Relationship between Cigarette Smoking and Cancer Characteristics and Survival among Breast Cancer Patients.

Carcinogenic effects of tobacco smoke may affect breast tumorigenesis. To assess whether cigarette smoking is associated with breast cancer characteristics, we investigated the relationships between smoking, pathological characteristics, and outcomes in 2153 women diagnosed with breast cancer 2001-2016. Patients were classified as never, former, or current smokers at the time of diagnosis. Logistic regression and multivariable Cox proportional hazards analysis were performed to determine whether smoking was associated with tumor characteristics. Multivariable Cox proportional hazards analysis was conducted to compare former or current smokers to never smokers in survival with adjustment for the potential confounders. The majority of women (61.8%) never smoked, followed by former smokers (26.2%) and current smokers (12.0%). After adjustment for demographic variables, body mass index, and comorbidities, tumor characteristics were not significantly associated with smoking status or pack-years smoked. Ten-year overall survival was significantly lower for former and current smokers compared to never smokers (p = 0.0105). However, breast cancer specific survival did not differ significantly between groups (p = 0.1606). Although cigarette smoking did not alter the underlying biology of breast tumors or breast cancer-specific survival, overall survival was significantly worse in smokers, highlighting the importance of smoking cessation in the recently diagnosed breast cancer patient.

Importance of IGF-I levels in IVF: potential relevance for growth hormone (GH) supplementation.

PURPOSE: Growth hormone (GH) supplementation in association with in vitro fertilization (IVF) is worldwide again increasing, even though study outcomes have been discrepant. Since GH acts via insulin-like growth factor-1 (IGF-1), its utilization in IVF would only seem to make sense with low IGF-1. We, therefore, determined whether IGF-I levels affect IVF outcomes. METHODS: Retrospectively, 302 consecutive first fresh, non-donor IVF cycles were studied, excluding patients on GH supplementation. Patients were divided into 3 subgroups: IGF-1 in lower 25th percentile (group A, < 132 ng/mL, n = 64); 25th-75th percentile (B, 133-202 ng/mL, n = 164), and upper 25th percentile (C, > 202 ng/mL, n = 74). IGF-1 was tested immunochemiluminometric with normal range at 78-270 ng/mL. Because of the study patients' adverse selection and low pregnancy chances, the main outcome measure for the study was cycle cancellation. Secondary outcomes were oocyte numbers, embryos transferred, pregnancies, and live births. RESULTS: Group A was significantly older than B and C (P = 0.019). IGF-1 decreased with increasing age per year by 2.2 ± 0.65 ng/mL (P = 0.0007). FSH was best in group B and worst in A (trend, P = 0.085); AMH was best in B and worst in A (N.S.). Cycle cancellations were lowest in C (11.6%) and highest in A (25.0%; P = 0.042). This significance further improved with age adjustment (P = 0.021). Oocytes, embryo numbers, pregnancies, and live birth rates did not differ, though oocyte numbers trended highest in B. CONCLUSIONS: Here presented results support the hypothesis that IGF-1 levels affect IVF outcomes. GH treatments, therefore, may be effective only with low IGF-1.

Predictive value of cytoplasmic granulation patterns during in vitro fertilization in metaphase II oocytes: part II, donor oocyte cycles.

OBJECTIVE: To determine whether the ooplasm granulation patterns of donor oocytes, like those of oocytes from poor-prognosis patients, are predictive of in vitro fertilization (IVF) outcomes. DESIGN: Retrospective cohort study. SETTING: Academically affiliated private clinical infertility and research center. PATIENT(S): 770 fresh and 381 vitrified-thawed metaphase II oocytes from young donors (aged 21.0-34.6 years) used for IVF during 2017-2020. INTERVENTION(S): Determination of granulation patterns in every oocyte during intracytoplasmic sperm injection as fine, central, uneven, dispersed, and peripheral (thawed only). MAIN OUTCOME MEASURE(S): Fertilization, pregnancy, and live birth rates in fresh and thawed donor oocytes. Both overall and known-outcome analyses were performed for pregnancy and live birth. RESULT(S): In fresh donor oocytes, 2 pronuclei rates trended down from 96.1% to 90.2%, 88.9%, and 69.7% from fine to central, uneven, and dispersed granulations; overall pregnancy rates trended down from 50.4% to 29.0%, 17.7%, and 6.9%, as well as live birth rates (43.4%, 21.6%, 12.5%, and 6.4%), from fine to uneven, central, and dispersed granulations. Known pregnancy and known-live birth analyses showed similar findings. Thawed donor oocytes demonstrated similar trends in differences in fertilization, pregnancy, and live birth analyses with relatively worse outcomes. Peripheral granulation, unique to vitrification and thawing, always demonstrated the worst IVF outcomes. Moreover, granulation patterns were relatively disassociated from embryo morphological grades in fresh and largely disassociated in thawed donor oocytes. CONCLUSION(S): Predictive values of oocyte granulation patterns for fertilization, pregnancy, and live birth in IVF cycles are even more pronounced in young donors than results in older poor-prognosis patients, further supporting integration of oocyte granulation patterns into embryo selection.

Predictive value of cytoplasmic granulation patterns during in vitro fertilization in metaphase II oocytes: Part I, poor-prognosis patients.

OBJECTIVE: To determine whether 4 cytoplasmic granulation patterns of human metaphase II oocytes have a predictive value for in vitro fertilization outcomes. DESIGN: A retrospective cohort study. SETTING: An academically affiliated private clinical infertility and research center. PATIENT(S): A total of 2,690 consecutive fresh autologous oocytes collected from women aged 41.2 ± 5.0 years between 2017 and 2019. INTERVENTION(S): Determination of granulation pattern in every oocyte during intracytoplasmic sperm injection as fine, central, dispersed, and newly introduced uneven granulations. MAIN OUTCOME MEASURE(S): Fertilization outcomes (2 pronuclei [2PN], <2PN, and >2PN rates), pregnancy, and live birth rates for different granulation patterns at different ages. RESULT(S): Fine granulation produced the highest 2PN rate, followed by central, uneven, and dispersed granulation (91.8%, 83.9%, 77.9%, and 54.8%, respectively). Differences in fertilization were surprisingly relatively independent of age and other variables. Overall, compared with fine granulation, dispersed granulation resulted in lower pregnancy rates (4.6% vs. 10.7%) and known-outcome analysis (1.3% vs. 5.6%) as well as lower live birth rates (3.0% vs. 8.9%) and known-outcome analysis (0.6% vs. 5.6%). The known-outcome analysis demonstrated that uneven granulation had lower live birth rates than fine granulation (2.3% vs. 5.6%). Unexpectedly, the ooplasm granulation patterns were largely disassociated from embryo morphologic grades. CONCLUSION(S): We, for the first time, demonstrated that 4 distinct cytoplasmic granulation patterns in metaphase II oocytes had, largely independent of age and other variables, a predictive value for fertilization, pregnancy, and live birth outcomes in in vitro fertilization cycles of poor-prognosis patients. These data suggest that upstream ooplasm granulation patterns deserve closer attention in terms of embryo selection.

Rate of rebound in follicle growth after cessation of ovarian stimulation in initial non-responders: a prospective cohort study.

Previously anecdotally observed rebounds in follicle growth after interruption of exogenous gonadotropins in absolute non-responders were the impetus for here reported study. In a prospective cohort study, we investigated 49 consecutive patients, absolutely unresponsive to maximal exogenous gonadotropin stimulation, for a so-called rebound response to ovarian stimulation. A rebound response was defined as follicle growth following complete withdrawal of exogenous gonadotropin stimulation after complete failure to respond to maximal gonadotropin stimulation over up to 5-7 days. Median age of study patients was 40.5 ± 5.1 years (range 23-52). Women with and without rebound did not differ significantly (40.0 ± 6.0 vs. 41.0 ± 7.0 years, P = 0.41), with 24 (49.0%) recording a rebound and 25 (51.0%) not. Among the former, 21 (87.5%) reached retrieval of 1-3 oocytes and 15 (30.6%) reached embryo transfer. A successful rebound in almost half of prior non-responders was an unsuspected response rate, as was retrieval of 1-3 oocytes in over half of rebounding patients. Attempting rebounds may, thus, represent another incremental step in very poor prognosis patients before giving up on utilization of autologous oocytes. Here presented findings support further investigations into the underlying physiology leading to such an unexpectedly high rebound rate.

A form of secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism as new infertility diagnosis.

BACKGROUND: Mediated via the androgen receptor on granulosa cells, models of small growing follicle stages demonstrate dependence on testosterone. Androgen deficiency reduces ovarian response to follicle stimulation hormone (FSH), granulosa cell mass and estradiol (E2) production falls and FSH, therefore, rises. Though potentially of adrenal and/or ovarian origin, androgen deficiency in association with female infertility is almost universally primarily of adrenal origin, raising the possibility that women with presumptive diagnosis of primary ovarian insufficiency (POI), also called primary ovarian failure (POF) may actually suffer from secondary ovarian insufficiency (SOI) due to adrenal hypoandrogenism that leads to follicular arrest at small-growing follicle stages. METHODS: This retrospective cohort study was performed in a private, academically affiliated infertility center in New York City. We searched the center's anonymized electronic research data bank for consecutive patients who presented with a diagnosis of POI, defined by age <41 year, FSH > 40.0 mIU/mL, amenorrhea for at least 6 month, and low testosterone (T), defined as total T (TT) in the lowest age-specific quartile of normal range. This study did not include patients with oophoritis. Since dehydroepiandrosterone sulfate (DHEAS) is the only androgen almost exclusively produce by adrenals, adrenal hypoandrogenism was defined by DHEAS < 100ug/dL. Thirteen of 78 presumed POI women (16.67%) qualified and represented the original study population. POI patients are usually treated with third-party egg donation; 6/13, however, rejected egg donation for personal or religious reasons and insisted on undergoing at least one last IVF cycle attempt (final study population). In preparation, they were supplemented with DHEA 25 mg TID and CoQ10 333 mg TID for at least 6 weeks prior to ovarian stimulation for IVF with FSH and human menopausal gonadotropins (hMG). Since POI patients are expected to be resistant to ovarian stimulation, primary outcome for the study was ovarian response, while secondary outcome was pregnancy/delivery. RESULTS: Though POI/POF patients usually are completely unresponsive to ovarian stimulation, to our surprise, 5/6 (83.3%) patients demonstrated an objective follicle response. In addition, 2/6 (33.3%) conceived spontaneously between IVF cycles, while on DHEA and CoQ10 supplementation and delivered healthy offspring. One of those is currently in treatment for a second child. CONCLUSIONS: This preliminary report suggests that a surprising portion of young women below age 41, tagged with a diagnosis of POI/POF, due to adrenal hypoandrogenism actually suffer from a form of SOI, at least in some cases amenable to treatment by androgen supplementation. Since true POI/POF usually requires third-party egg donation, correct differentiation between POI and SOI in such women appears of great importance and may warrant a trial stimulation after androgen pre-supplementation for at least 6 weeks.

Euploid miscarriage is associated with elevated serum C-reactive protein levels in infertile women: a pilot study.

PURPOSE: Increased serum C-protein (CRP) levels reduce fecundity in healthy eumenorrheic women with 1-2 pregnancy losses. Subclinical systemic inflammation may impede maternal immune tolerance toward the fetal semi-allograft, compromising implantation and early embryonic development. Some miscarriages with normal karyotypes could, therefore, be caused by inflammation. Whether pre-pregnancy CRP relates to karyotypes of spontaneously aborted products of conception (POCs) was investigated. METHODS: A study cohort of 100 infertile women with missed abortions who underwent vacuum aspirations followed by cytogenetic analysis of their products of conception tissue was evaluated at an academically affiliated fertility center. Since a normal female fetus cannot be differentiated from maternal cell contamination (MCC) in conventional chromosomal analyses, POC testing was performed by chromosomal microarray analysis. MCC cases and incomplete data were excluded. Associations of elevated CRP with first trimester pregnancy loss in the presence of a normal fetal karyotype were investigated. RESULTS: Mean patients' age was 39.9 ± 5.8 years; they demonstrated a BMI of 23.9 ± 4.6 kg/m2 and antiMullerian hormone (AMH) of 1.7 ± 2.4 ng/mL; 21.3% were parous, 19.1% reported no prior pregnancy losses, 36.2% 1-2 and 6.4% ≥ 3 losses. Karyotypes were normal in 34% and abnormal in 66%. Adjusted for BMI, women with elevated CRP were more likely to experience euploid pregnancy loss (p = 0.03). This relationship persisted when controlled for female age and AMH. CONCLUSIONS: Women with elevated CRP levels were more likely to experience first trimester miscarriage with normal fetal karyotype. This relationship suggests an association between subclinical inflammation and miscarriage.

Effects of dehydroepiandrosterone (DHEA) supplementation on sexual function in premenopausal infertile women.

PURPOSE: To investigate the effects of dehydroepiandrosterone (DHEA) supplementation on female sexual function in premenopausal infertile women of advanced ages. METHODS: This observational study was conducted in an academically affiliated private fertility center. Patients included 87 premenopausal infertile women, 50 of whom completed the study including the Female Sexual Function Index (FSFI) questionnaires and comprehensive endocrine evaluation before and 4-8 weeks after initiating 25 mg of oral micronized DHEA TID. RESULTS: Age of patients was 41.1 ± 4.2 years, BMI 24.4 ± 6.1 kg/m2, 86% were married, and 42% were parous. Following supplementation with DHEA, all serum androgen levels increased (each P < 0.0001), while FSH levels decreased by 2.6 ± 4.4 from a baseline of 10.3 ± 5.4 mIU/mL (P = 0.009). The FSFI score for the whole study group increased by 7% (from 27.2 ± 6.9 to 29.2 ± 5.6; P = 0.0166). Domain scores for desire increased by 17% (P = 0.0004) and by 12% for arousal (P = 0.0122); lubrication demonstrated an 8% trend towards improvement (P = 0.0551), while no changes in domain scores for orgasm, satisfaction, or pain were observed. Women in the lowest starting FSFI score quartile (<25.7), experienced a 6.1 ± 8.0 (34%) increase in total FSFI score following DHEA supplementation. Among these women, improvements in domain categories were noted for desire (40%), arousal (46%), lubrication (33%), orgasm (54%), satisfaction (24%), and pain (25%). CONCLUSIONS: This uncontrolled observational study implies that supplementation with DHEA improves sexual function in older premenopausal women with low baseline FSFI scores.