Breast Cancer and Fertility Preservation in Young Female Patients: A Systematic Review of the Literature.

INTRODUCTION: Breast cancer affects almost 1.5 million women worldwide below the age of 45 years each year. Many of these women will be advised to undergo adjuvant chemotherapy to minimize the risk of death or recurrence of the tumor. For these patients, chemotherapy is a known cause of infertility, as it can damage primordial follicles, which can lead to early menopause or premature ovarian insufficiency. This systematic review aims to synthesize the current evidence of the most suitable treatments for fertility preservation. METHODOLOGY: This review was performed following the PRISMA guidelines. The authors conducted an extensive search from the last 15 years. Relevant studies were pursued in PubMed, Embase, and the Cochrane Library up until 31 July 2023. A total of seven eligible studies were identified. RESULTS: From the reviewed literature, ovarian suppression with gonadotropin-releasing hormone agonists showed promising results in preserving fertility for breast cancer patients undergoing chemotherapy. Additionally, oocyte and embryo cryopreservation demonstrated successful outcomes, with embryo cryopreservation being the most effective option. Notably, the slow-freezing and vitrification methods were both effective in preserving embryos, with vitrification showing superior results in clinical-assisted reproductive technologies. Ovarian tissue cryopreservation emerged as a viable option for prepubertal girls and those unable to undergo conventional ovarian stimulation. The potential of in vitro maturation (IVM) as an alternative method presents a promising avenue for future fertility preservation research. DISCUSSION: The most suitable treatments for fertility preservation in young patients is the temporary suppression with luteinizing hormone-releasing analogs, while the patient undergoes chemotherapy and cryopreservation. For cryopreservation, the physicians might deem it necessary to either cryopreserve ovarian tissue taken from the patient before any treatment or cryopreserve embryos/oocytes. Cryopreservation of oocytes and/or embryos is the most effective solution for fertility preservation in women of reproductive age, who have a sufficient ovarian reserve and are diagnosed with breast cancer, regardless of the histological type of the tumor. Because approximately 50% of young breast cancer patients are interested in becoming pregnant right after completion of therapy, the evolution and development of fertility preservation techniques promise to be very exciting.

Reverse Onco-Cardiology: What Is the Evidence for Breast Cancer? A Systematic Review of the Literature.

Breast cancer and cardiovascular diseases (CVD) represent significant global health challenges, with CVD being the leading cause of mortality and breast cancer, showing a complex pattern of incidence and mortality. We explore the intricate interplay between these two seemingly distinct medical conditions, shedding light on their shared risk factors and potential pathophysiological connections. A specific connection between hypertension (HTN), atrial fibrillation (AF), myocardial infarction (MI), and breast cancer was evaluated. HTN is explored in detail, emphasizing the role of aging, menopause, insulin resistance, and obesity as common factors linking HTN and breast cancer. Moreover, an attempt is made to identify the potential impact of antihypertensive medications and highlight the increased risk of breast cancer among those women, with a focus on potential mechanisms. A summary of key findings underscores the need for a multisystem approach to understanding the relationship between CVD and breast cancer is also explored with a highlight for all the gaps in current research, such as the lack of clinical observational data on MI and breast cancer in humans and the need for studies specifically designed for breast cancer. This paper concludes that there should be a focus on potential clinical applications of further investigation in this field, including personalized prevention and screening strategies for women at risk. Overall, the authors attempt to provide a comprehensive overview of the intricate connections between breast cancer and cardiovascular diseases, emphasizing the importance of further research in this evolving field of cardio-oncology.

Fertility status in childhood cancer survivors of hematological malignancies: a systematic review.

Stunning advances in treatment modalities implemented in children with hematological malignancies have led to 5-year overall survival rates exceeding 85%. However, this growing population of long-term survivors has raised significant concerns about their fertility status throughout adulthood, while specific treatment- and non-treatment-related factors appear to possibly affect fertility through distinct mechanisms. We aimed to comprehensively review the published literature on the association between treatment-related factors and risk of impaired fertility in childhood hematological cancer survivors. We searched PubMed up to March 2021 to identify eligible studies published during the last two decades. A narrative synthesis of the results was performed, although no meta-analysis was feasible due to the small number of studies and the large heterogeneity of evidence. Five studies on 2020 survivors of childhood leukemia were deemed eligible. The qualitative data synthesis showed significant fertility deficits in survivors treated with cranial radiotherapy and chemotherapy for childhood leukemia. Two studies examined biochemical measures of reduced ovarian reserve, providing some evidence that the levels of anti-Müllerian hormone can be used as a proxy for diminished ovarian reserve. The current findings should facilitate the delivery of age- and gender-appropriate interventions to optimize reproductive outcomes in childhood hematological cancer survivors.

Effect of Aromatase Inhibitors on Serum Calprotectin Levels in an Animal Experimental Model: Trial.

BACKGROUND/AIM: Utilizing an experimental animal model, we investigated the correlation between aromatase inhibitors (AIs) (anastrozole and letrozole) and Calprotectin levels. AIs have demonstrated superior efficacy when used as adjuvant endocrine therapy or monotherapy for postmenopausal patients with hormone receptor (HR)-positive early-stage breast cancer, although various side effects have been recorded. MATERIALS AND METHODS: Fifty-five adult female Wistar rats were randomized and assigned into four groups. The control group received no intervention. The other three groups were subjected to ovariectomy, and serum Calprotectin levels were measured at baseline, 2, and 4 months. In addition, glucose, total cholesterol, very low-density lipoprotein- (VLDL-) cholesterol, low-density lipoprotein (LDL-) cholesterol, high-density lipoprotein- (HDL-) cholesterol, and triglyceride levels were measured. Histological analysis of liver tissue was carried out following rats' euthanasia. RESULTS: Aromatase inhibitors (anastrozole and letrozole) affect calprotectin levels in ovariectomized rats. Calprotectin, a marker of inflammation, was found to be affected by the use of the inhibitors. CONCLUSION: The potential of hepatotoxicity can be examined by assessing the elevation of inflammation markers such as Calprotectin, which is an indicator that should be strictly taken into consideration when administering aromatase inhibitors as treatment.

Soy Isoflavones and Breast Cancer Risk: A Meta-analysis.

BACKGROUND/AIM: Soy contains genistein and daidzein isoflavones. Isoflavones are phytoestrogens, with a similarity in structure to human 17-ß estradiol hormone. They imitate the action of estrogen on organs by binding and activating estrogen receptors. Numerous studies have examined the relationship between soy consumption and breast cancer but not the amount of consumption itself. We performed a systematic review of the literature in order to determine whether the amount of soy and isoflavones consumed has a positive effect in pre- and post-menopausal women. MATERIALS AND METHODS: Data gathering was performed following PRISMA guidelines. Narrowing down the result set for all relevant data was performed via title, abstract, full-text evaluation and the snowball procedure. The selected articles had all relevant data extracted. Analysis of the data was performed using Cochrane's Review Manager statistical analysis tool in order to draw conclusions regarding the positive effect for the amount of soy and isoflavones consumed. RESULTS: Significant results were found when statistically analyzing data from prospective studies which compared soy isoflavones consumption, breast cancer risk and occurrence. The data were indicative of a clear inverse correlation between the amount of isoflavones consumed and breast cancer occurrence in pre- and post-menopausal women. CONCLUSION: The consumption of soy isoflavones can reduce the risk of breast cancer in pre-menopausal and post-menopausal women.

The expression of Galectin-3 in endometrial cancer: a systematic review of the literature.

BACKGROUND: Galectin-3 is part of a protein group called lectins and acts as a multifunctional glycoprotein due to its expression location. Galectin-3 is expressed by different human tissues. It plays a significant role in carcinogenesis and the selection of tumor-related physiological and pathological activities. Galectin-3 has been utilized through the years as a diagnostic and prognostic marker for various types of cancers. METHODS AND RESULTS: This review describes the outcomes of some studies on the matter that were selected appropriately through a review of the existing literature. These studies examined the levels of Galectin-3 expression in endometrial carcinomas, the outcomes, and the prognosis of these carcinomas. Two of the studies concluded that high expression of Galectin-3 is associated with a tumor's histological grade, type and depth. This enhanced nuclear Galectin-3 expression might assist in progression to atypia and neoplasia. The other three on the contrary concluded that malignant tumors had a decreased expression of Galectin-3 and that Galectin-3 played a suppressive role in tumor growth. CONCLUSIONS: The part Galectin-3 might potentially have in metastasis of cancers and the offering of a better prognosis for patients is of high importance. To date, there is minimal literature regarding the effects of Galectin-3 and more research is required.

Demographic, clinical and hormonal characteristics of patients with premature ovarian insufficiency and those of early menopause: data from two tertiary premature ovarian insufficiency centers in Greece.

The aim of the study was to compare demographic, hormonal and clinical parameters in patients with premature ovarian insufficiency (POI) and women with early menopause in Greece. One hundred thirty-nine women of Greek origin, aged 14-45 years, referring for oligomenorrhea and having elevated FSH concentrations were divided into three groups regarding the age of menstrual disturbances onset [POI1:

Endometrial CRH and implantation: from bench to bedside.

Endometrial corticotropin-releasing hormone (CRH) has been described as a mediator of decidualisation and as a contributor of maternal-fetal immunotolerance. Deregulation of the CRH expression pattern has been associated with unfavourable reproductive outcomes as well as chronic endometrium-derived inflammatory disorders, such as endometriosis and adenomyosis. The current review summarises the evidence produced regarding the role of CRH in endometrial physiology and pathophysiology and highlights recent clinical data regarding the role of CRH in improving clinical pregnancy rates in women with repeated implantation failures following in vitro fertilisation and embryo transfer.

The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence.

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes.

Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement.

CONTEXT: Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD). OBJECTIVE: The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women. DESIGN AND SETTING: This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland). PARTICIPANTS: Young women with primary ovarian insufficiency participated in the study. INTERVENTIONS: We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 µg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 µg/d) or placebo. MAIN OUTCOME MEASURE: Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry. RESULTS: At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well. CONCLUSION: Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.

Metformin reduces the expression of corticotropin-releasing hormone and urocortin in the endometrium of healthy women.

OBJECTIVE: To investigate the effect of metformin administration on the expression of endometrial corticotrophin-releasing hormone (CRH) and urocortin (UCN) in the midluteal phase of the cycle. DESIGN: Experimental study, performed in 2010-2011. SETTING: University hospital. PATIENT(S): Eight healthy, normally cycling and parous women volunteered for the study. INTERVENTION(S): All women were investigated in two nonconsecutive cycles (control cycle, untreated and after one cycle break; trial cycle, oral administration of metformin [850 mg × 2]). Endometrial pipelle biopsies were obtained on day LH+7. MAIN OUTCOME MEASURE(S): The endometrial biopsies were immunohistochemically assessed for CRH and UCN expression. Evaluation of positivity was performed by applying the immunoreactive score. RESULT(S): Compared with samples from control cycles, CRH and UCN were significantly reduced in endometrial samples obtained during metformin treatment. This down-regulation was significant both in the endometrial cells and in the endometrial stroma. CONCLUSION(S): This is the first study showing that during the midluteal phase of the cycle, metformin may decrease the production of CRH and UCN in the endometrium. Metformin interference to decidualization could happen by CRH/UCN modification.

Increased vascular inflammation in early menopausal women is associated with hot flush severity.

CONTEXT: Menopause has been related to an increased atherosclerotic risk. Presence and severity of hot flushes in menopausal women have been associated with impaired endothelial function and advanced subclinical atherosclerosis. OBJECTIVE: The objective of the study was to evaluate the effect of menopausal transition on vascular inflammation indices and investigate the association of hot flush severity with these indices in early menopausal women. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women (controls). MAIN OUTCOMES: Serum high-sensitivity C-reactive protein, P-selectin, and soluble CD40 ligand (sCD40L) levels were measured. RESULTS: P-selectin and sCD40L were increased in early menopausal compared with control women (P = 0.006 and P = 0.02 respectively), whereas high-sensitivity C-reactive protein levels did not differ (P = 0.4) between the groups. Hot flush severity was the most important independent predictor of P-selectin levels (P = 0.011) in early menopausal women. Women with moderate/severe/very severe hot flushes had increased P-selectin compared with women with no/mild hot flushes or controls (P < 0.05 for both). The sCD40L levels were also higher in menopausal women with moderate/severe/very severe hot flushes compared with controls (P = 0.03) but did not differ significantly compared with women with no/mild hot flushes (P = 0.2). CONCLUSIONS: Increased indices of vascular inflammation in early menopausal compared with age-matched premenopausal women may indicate a higher atherosclerotic risk. Increased severity of hot flushes was associated with adverse changes in vascular inflammation, further supporting the emerging role of hot flushes in cardiovascular prognosis in these women.

Short-term hormone therapy improves sCD40L and endothelial function in early menopausal women: potential role of estrogen receptor polymorphisms.

OBJECTIVE: Hormone therapy (HT) has been suggested to improve vascular function and inflammation in menopausal women, although not consistently. We aimed to investigate the effects of HT on endothelial function and inflammation, especially sCD40L, in early menopausal women, and the effect of common estrogen receptor (ER) polymorphisms on vascular responses to HT. STUDY DESIGN: Eighty-four early menopausal women (<3 years in menopause) with menopausal complaints eligible for HT. Forty women received transdermal 17ß-estradiol plus cyclical micronized progesterone for 3 months while 44 did not (controls). MAIN OUTCOME MEASURES: Brachial artery flow-mediated dilation (FMD) and vascular inflammation markers (sICAM, sP-Selectin and sCD40L). Genetic polymorphisms of ERα (PvuII 454-397T>C and XbaI 454-351A>G) and ERß (AluI 1730A>G) were also assessed. RESULTS: The two groups did not differ at baseline. Following HT, vasomotor complaints' severity, blood pressure, LDL, sCD40L, sICAM and sP-Selectin decreased and FMD increased compared to controls (P<0.05 for all). ERß AluI A allele presence was the most important independent predictor of HT-induced increase in FMD while ERα XbaI A allele was the only independent predictor of decrease in sCD40L. CONCLUSIONS: Short-term HT in early menopausal women improved endothelial function and inflammation. Specific ER polymorphisms that were found to be main determinants of HT-induced effects on endothelium could identify subgroups of women who may benefit the most from HT.

Effect of ethinylestradiol/cyproterone acetate on endothelial function in young non-obese women with polycystic ovary syndrome: a pilot study.

BACKGROUND: Combined oral contraceptives are used in polycystic ovary syndrome (PCOS) women for the treatment of hyperandrogenism and menstrual cycle disturbances. AIM: To assess the effect of ethinylestradiol and cyproterone acetate (EE/CA) on endothelial function in young, non-obese PCOS women in a pilot study. METHODS: Thirteen young, non-obese PCOS women (20.9 ± 3.7 years, 23.0 ± 4.0 kg/m(2)) received 35 mcg EE & 2 mg CA for 6 months. Fourteen age- and body mass index (BMI)-matched healthy women served as controls. Endothelial function assessed by brachial artery flow-mediated dilation (FMD), indices of hyperandrogenism, and insulin resistance were studied at baseline and 6-month follow-up. RESULTS: FMD was impaired in PCOS compared to control women (4.67 ± 2.38% vs. 10.12 ± 3.19%, p < 0.001), but increased significantly following EE/CA (9.99 ± 2.11%, p < 0.001 vs. baseline), reaching normal values (p = NS vs. controls). EE/CA also significantly decreased hyperandrogenism indices and increased total and HDL cholesterol and triglycerides (p < 0.05 vs. baseline). The only independent predictor of treatment-induced FMD improvement in PCOS women was the decrease in free androgen index. CONCLUSIONS: Treatment with combination of estrogens and antiandrogens reverses endothelial dysfunction in young, non-obese PCOS women mainly via improving hyperandrogenism. Further research is needed to investigate whether this treatment may also reduce cardiovascular risk in these women.

Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: a prospective randomized study.

OBJECTIVE: To compare the effect of two different insulin sensitizers, metformin and pioglitazone, on endothelial function in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective randomized study. SETTING: University Hospital endocrinology outpatient clinic. PATIENT(S): Young women with PCOS (aged 23.3±4.9 years). INTERVENTION(S): Patients were assigned randomly to no treatment (n=14), metformin 850 mg two times per day (n=15), and pioglitazone 30 mg daily (n=14) for 6 months. Healthy age- and body mass index-matched women served as controls (n=14). MAIN OUTCOME MEASURE(S): Brachial artery flow-mediated dilation was studied at baseline and 6 months. RESULT(S): Women with PCOS had higher insulin resistance and hyperandrogenism indices and lower flow-mediated dilation compared with controls. The three groups of women with PCOS did not differ at baseline. No differences were observed at follow-up in women who received no treatment. Metformin and pioglitazone improved flow-mediated dilation to a similar extent, restoring it to normal values at 6 months. Both insulin sensitizers induced favorable changes in insulin resistance and hyperandrogenism indices in women with PCOS. Independent predictors of flow-mediated dilation improvement at 6 months were treatment with insulin sensitizers and reduction in insulin resistance. CONCLUSION(S): In young women with PCOS, treatment with metformin or pioglitazone for 6 months induces a similar beneficial effect on endothelial function; this may be partially attributed to an improvement in insulin resistance. Further research is needed to investigate whether treatment with insulin sensitizers in women with PCOS also reduces cardiovascular risk.

Endothelial function, but not carotid intima-media thickness, is affected early in menopause and is associated with severity of hot flushes.

CONTEXT: The effect of early menopause on indices of vascular function has been little studied. OBJECTIVE: The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women. MAIN OUTCOME MEASURES: Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ERbeta (rs4986938 A-->G) polymorphisms were studied in menopausal women. RESULTS: FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. CONCLUSIONS: Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause.

Cardiovascular effects of endogenous estrogen and hormone therapy.

The incidence of cardiovascular disease is low in healthy premenopausal women and increases with age especially after the menopause; this difference has been attributed to the loss of endogenous estrogen. Atherosclerosis is a chronic inflammatory condition of the vascular wall that may result in an acute clinical event by inducing plaque rupture/erosion leading to thrombosis. A growing body of evidence suggests that the spectrum of the effects of estrogen on vascular pathophysiology is complex and may depend largely on the state of vascular pathology. In relatively healthy vessels, estrogen prevents the development and progression of atherosclerotic lesions, while in the presence of established atherosclerotic plaques, estrogen fails to inhibit the progression of atherosclerosis or may even trigger cardiovascular events. The mechanisms responsible for this are not yet fully elucidated. It is possible that postmenopausal estrogen/progestogen therapy may be beneficial in perimenopausal and early menopausal women prior to atherosclerotic plaque formation, but it may not prevent progression of atherosclerotic plaques and acute cardiovascular events in older women with cardiovascular risk factors or women with established atherosclerosis. Various formulations, doses and routes of hormone therapy administration as well as the genetic background of women should also be taken into account when considering the benefit-to-risk ratio of hormone therapy use.

Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency.

OBJECTIVE: To assess sexual function in women with spontaneous 46,XX primary ovarian insufficiency after at least 3 months of a standardized hormone replacement regimen. DESIGN: Cross-sectional cohort, controlled. SETTING: National Institutes of Health Clinical Research Center. PATIENT(S): Women with primary ovarian insufficiency (n = 143) and regularly menstruating controls (n = 70). INTERVENTION(S): Self-administered questionnaires, 100 microg/day E(2) patch, oral medroxyprogesterone acetate 10 mg for 12 days each month for patients. MAIN OUTCOME MEASURE(S): Derogatis Interview for Sexual Function Self-Report (DISF-SR). RESULT(S): Women with primary ovarian insufficiency had significantly lower DISF-SR composite scores compared with control women. Their serum total testosterone levels were significantly correlated with DISF-SR composite score, although this accounted for only 4% of the variance in this measure. Patients with testosterone levels below normal tended to have lower DISF-SR composite scores. Of patients with primary ovarian insufficiency, 9 of 127 (7%) scored below the second percentile on the composite sexual function score, compared with 1 of 49 control women (2%). CONCLUSION(S): As assessed by the DISF-SR, sexual function is in the normal range for most young women with 46,XX spontaneous primary ovarian insufficiency who are receiving physiologic E(2) replacement. However, as a group, these young women score significantly lower on this sexual function scale than control women.

Reproductive corticotropin releasing hormone, implantation, and fetal immunotolerance.

The fundamental process of implantation involves a series of steps leading to effective cross-talk between invasive trophoblast cells and the maternal endometrium. The molecular interactions at the embryo-maternal interface during the time of blastocyst adhesion and subsequent invasion are not fully understood. Embryonic trophoblast and maternal decidual cells produce corticotropin-releasing hormone (CRH) and express Fas ligand (FasL), a proapoptotic cytokine. Fas and its ligand are pivotal in the regulation of immune tolerance. Trophoblast and decidual CRH play crucial roles in implantation, as well as in the anti-rejection process that protects the fetus from the maternal immune system, primarily by killing activated T cells through Fas-FasL interaction. The potential use of CRH antagonists is presently under intense investigation. CRH antagonists have been used experimentally to elucidate the role of CRH in blastocyst implantation and invasion, early fetal immunotolerance, and premature labor.

Testosterone therapy in premenopausal women.

Testosterone therapy for postmenopausal women and women with surgical menopause, albeit controversial, is becoming more widespread. However, only limited data are available to support its use in premenopausal women. Androgens have important biological roles in young women, influencing bone and muscle mass, mood and well-being, and libido. Pathophysiological states affecting ovarian and adrenal function or both may result in androgen deficiency in premenopausal women. Young women with hypothalamic amenorrhea, premature ovarian failure, oophorectomy, premenstrual syndrome, acquired immunodeficiency wasting syndrome, adrenal insufficiency, and hypopituitarism may have testosterone deficiency. Young women with loss of libido may also have testosterone deficiency. Medications that may lead to testosterone insufficiency include oral estrogen, oral contraceptives, and corticosteroids. Testosterone deficiency in young women may be underdiagnosed because the symptoms generally are nonspecific and the measurement of total and free testosterone is inaccurate with commonly used techniques. Only a few studies investigating the effects of testosterone therapy have been performed thus far in premenopausal women. Long-term trials evaluating safety and effectiveness of testosterone therapy in premenopausal women are lacking. Common adverse effects include hirsutism and acne, which reverse with discontinuation of treatment. The availability of testosterone regimens specifically designed for women is expected to help maintain testosterone levels within the normal range and clarify whether the apparent beneficial effects of testosterone therapy are physiological or pharmacological.