Ovarian Failure In Young Women Research Articles

Serum androgen dynamics in young women aged 18-40 treated with chemotherapy for breast cancer: an observational, multicentric, prospective study in France

Although the deleterious impact of chemotherapy regimen used to treat women of reproductive age with breast cancer on ovarian reserve has been extensively studied, hardly anything has been reported on the effect of these protocols on theca cell function and ovarian androgen secretion. The aim of this prospective multicentric cohort study was to describe serum levels of total testosterone and androstenedione during chemotherapy and 24-month follow-up in 250 patients <40 years treated for breast cancer. Mean basal levels of androstenedione and total testosterone at diagnosis were 1.68 ng/mL and 0.20 ng/mL respectively. No correlation with age was found. Serum levels of androstenedione and total testosterone rapidly decreased after chemotherapy completion, before slowly increasing and almost returning to basal levels in all patients during 2-year follow-up. In conclusion our study demonstrates a chemotherapy-induced alteration of ovarian thecal function, resulting in a significant decrease in serum androgen levels. This alteration of theca cell function adds to the well-known alteration of granulosa cell function, resulting in a global, but partly transient, ovarian failure in young women treated for breast cancer. These data bring new insight into ovarian physiology and emphasize the need for pre and post-treatment ovarian follow-up. Trial registration: ClinicalTrial.gov identifier NCT01114464

Chemotherapy-induced ovarian failure in young women with early breast cancer: Prospective analysis of four randomised neoadjuvant/adjuvant breast cancer trials

BackgroundYoung women receiving chemotherapy for early breast cancer (EBC) have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is insufficiently reliable and reproducible. We analysed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, CIA, and antral follicle count (AFC). MethodsBlood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neoadjuvant/adjuvant trials were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed oestradiol (cutoff <52.2 ng/L) and follicle-stimulating hormone (cutoff >12.4IU/L) were used to define CIOF for patients with baseline premenopausal hormone levels, anti-Müllerian hormone (AMH), and AFC to assess ovarian reserve. Further analyses included CIA, regain of premenopausal hormone levels, and disease-free survival (DFS) also in subgroups. ResultsSix hundred ninety-six patients aged ≤45 years had premenopausal hormone levels at baseline. Overall, 85.1% (592/696) experienced CIOF at EOT, and 147 of 592 had further hormone measurements after EOT. Of those, 32.7% (48/147) regained premenopausal hormone levels after 6 months, 57.9% (66/114) regained premenopausal hormone levels after 12 months, 83.0% (73/88) regained premenopausal hormone levels after 18 months, and 89.2% (74/83) regained premenopausal hormone levels after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Four-year DFS without CIOF versus CIOF was 65.9% versus 84.6% (hazard ratio [HR] = 2.09, 95% confidence interval [CI]: 1.37–3.19; P < 0.001); in hormone receptor positive 61.8% versus 87.5% (HR = 2.69, 95% CI: 1.57–4.60; P < 0.001); in <30 years 68.3% versus 92.6% (HR = 4.87, 95% CI: 1.05–22.63; P = 0.026). ConclusionMost premenopausal women experienced CIOF after chemotherapy for EBC. After 2 years, nearly all regain premenopausal hormone levels. CIOF was associated with better DFS, especially in patients with hormone receptor–positive EBC or aged <30 years.

Robotically Assisted Laparoscopic Ovarian Transposition in Women with Lower Gastrointestinal Cancer Undergoing Pelvic Radiotherapy.

Pelvic radiotherapy (RT) is a standard component of the management for patients with locally advanced rectal cancer or squamous cell carcinoma of the anus. Pelvic RT leads to permanent and irreversible ovarian failure in young women. This study aimed to determine the effectiveness of robotically assisted laparoscopic ovarian transposition (OT) before RT in women with rectal or anal cancer who wanted to preserve normal ovarian function. The study reviewed the medical records of all patients treated at our institution from August 2009 to October 2014 who received robotically assisted laparoscopic OT for rectal or anal cancer before RT. Clinical and hormonal data were abstracted to determine ovarian function. The study identified 22 women with rectal (n=20) or anal (n=2) cancer. The median age of the women was 39years (range 26-45years). For one patient, OT was technically not feasible. The postoperative course was uneventful in all but one case. Follow-up data on ovarian function were unavailable for 3 patients. The median times from RT initiation to the last gynecologic or hormonal evaluation were 9months (range 5-47 months) and 10.5months (range 5-47months), respectively. At the last gynecologic or hormonal follow-up visit, ovarian function was preserved in 12 (67%) of 18 evaluable patients, including 9 (90%) of 10 patients 40years of age or younger and 3 (38%) of 8 patients older than 40years (P=0.07). Robotically assisted laparoscopic bilateral OT is safe and can lead to preservation of ovarian function in two-thirds of patients with low gastrointestinal cancer undergoing pelvic RT. It should be considered in this setting, especially for women age 40years or younger, to avoid premature menopause and its associated sequelae.

Assessment of the effect of different vitrification solutions on human ovarian tissue after short-term xenotransplantation onto the chick embryo chorioallantoic membrane.

Chemotherapy can lead to the loss of fertility and premature ovarian failure in young women who suffer from malignant diseases. Freezing ovarian tissue by vitrification allows for the preservation of a large number of follicles prior to treatment, yet no established protocols have been optimized with respect to the vitrification solution. The aim of the present study was to evaluate the early stage of human ovarian tissue xenotransplantated onto the chick embryo chorioallantoic membrane after vitrification, and to determine the effect of different vitrification solutions on ovarian tissue quality-as defined by morphology and viability of follicles, neovascularization, cell proliferation, and apoptosis. Each vitrification protocol had a different impact on ovarian tissue at the early transplantation stage; one process using the lowest concentrations of ethylene glycol and dimethylsulfoxide, plus sucrose, demonstrated a moderate advantage compared to the other protocols. We also demonstrated that the chorioallantoic membrane model can be a useful alternative for short-term xenotransplantation studies of angiogenesis into human ovarian cortical tissue.

Primum Non Nocere.

Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned both due to the risk of postsurgical adhesions and the introduction of medical ovulation induction. Laparoscopic ovarian drilling (LOD) is an alternative method to induce ovulation in PCOS patients with clomiphene citrate resistance instead of gonadotropins. Surgical therapy with LOD may avoid or reduce the need for gonadotropins or may facilitate their use. However, the procedure, though effective, can be traumatic on the ovaries, which may cause postoperative adhesions and/or diminished ovarian reserve. In over-enthusiastic hands, this day-care procedure might lead to iatrogenic premature ovarian failure in young women. Some trials have compared LOD with gonadotropins, but, because of variations in study design and small sample size, the results are inconsistent and definitive conclusions about the relative efficacy of LOD and gonadotropins cannot be extracted from the individual studies. Today, evidence-based reviews conclude that there is no evidence of a significant difference in rates of clinical pregnancy, live birth or miscarriage in women with clomiphene-resistant PCOS undergoing LOD compared to other medical treatments. The reduction in multiple pregnancy rates in women undergoing LOD is the only pro-LOD argument. However, there are ongoing serious concerns about the long-term effects of LOD on ovarian function.

Gonadotropin-releasing hormone agonist may minimize premature ovarian failure in young women undergoing autologous stem cell transplantation

To compare the rate of premature ovarian failure (POF) after stem cell transplantation (SCT) in young women receiving GnRH-agonist (GnRH-a) in conjunction with gonadotoxic chemotherapy. Prospective, nonrandomized study. Tertiary university hospital. Ninety-five women received conditioning chemotherapy, with or without GnRH-a before SCT. Complete information was available for only 83 patients. Conditioning chemotherapy, with or without GnRH-a before SCT. Cyclic ovarian function (COF) or POF after SCT. There were no significant differences in age, chemotherapy treatment, or diagnoses between the study and control groups. In the GnRH-a group, 38.3% (18/47) patients resumed COF, compared with 11.1% (4/36) for patients who did not receive GnRH-a. Patients who resumed COF were on average 3.7 years (median, 3 years) younger at the time of transplantation than those who experienced POF. GnRH-a had a significant effect on long-term COF in patients with lymphomas (66.7% [14/21] for GnRH-a group vs. 18.2% [2/11] for control) but not for leukemia patients. GnRH-a cotreatment in conjunction with conditioning chemotherapy before SCT may significantly decrease the gonadotoxicity and POF from 82% to 33% in lymphoma but not in leukemia patients.

No Reduction of Ovarian Failure with the Use of GnRH-Analogues or Oral Contraceptives in Young Women Treated with Escalated BEACOPP for Advanced-Stage Hodgkin Lymphoma (HL). Final Results of the PROFE Trial, German Hodgkin Study Group (GHSG).

Abstract 3710Poster Board III-646 PurposeFor ongoing trials of the German Hodgkin Study Group (GHSG), the reduction of treatment-related toxicities is the main goal. In this respect, the prevention of ovarian failure in young women is of major importance. This might be achieved with oral contraceptives and Gonadotropin-releasing hormone agonistic analoges (GnRH-a) by inhibiting follicular growth in the ovary. Unfortunately, only contradictory, mostly retrospective or non-controlled results on these protective effects have been published, Thus, the GHSG started a randomised phase-II trial (PROFE) for the reduction of ovarian failure with the use of GnRH-analogues and oral contraceptives in young women treated with intensive chemotherapy for advanced-stage HL. The aim of the trial was to develop a standard co-treatment for the reduction of infertility rates. MethodsThe study was designed for young female patients (18-40 years) with advanced-stage HL, including stage II with B symptoms and one of the following risk factors: extranodal disease and/or large mediastinal mass, stage III, and IV. The patients were randomly assigned either to receive daily oral contraceptive or to receive the GnRH-analogue given monthly during 8 cycles of polychemotherapy with escalated BEACOPP. Blood samples were drawn for determination of hormonal levels once before the beginning of therapy, monthly during therapy, and 6, 12, and 18 months after therapy. Hormonal profiles including follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, Anti-Müllerian Hormone (AMH), prolactin, testosterone, DHEAS, SHBG, Inhibin A, Inhibin B, and progesterone were measured to document fertility status. The primary endpoint according to study protocol was the FSH level 6 months after the end of therapy. Because in the meantime AMH has been established as more valid indicator for ovarian function, we finally used AMH levels after minimally 12 months (<.46 μg/l) as more conclusive criterion for infertility. Individual courses for FSH, AMH and oestradiol in the 2 experimental groups will be presented. ResultsThe recruitment started in 2004 and was prematurely stopped in 2007 because of the following hindrances to participation: first, the application of the more intensive 8 cycles of escalated BEACOPP instead of less toxic treatment alternatives in the competing HD15 study (6 cycles of escalated BEACOPP or 8 cycles of BEACOPP-14). Second, to date, mostly all female patients in advanced stages already receive GnRH-analogue co-treatment, as recommended by their gynaecologists, and could therefore not be included into the PROFE trial. Consequently, a total of 23 patients are now evaluable for the final analysis of blood samples. Twelve patients were enrolled into arm A (oral contraceptive) and 11 into arm B (GnRH-analogue). At randomisation, women's mean age was 28 years in arm A and it was 26 years in arm B. FSH and AMH levels were correlated but also showed remarkable differences. In 8 cases FSH levels finally returned to normal values after therapy, whereas AMH levels remained reduced with exception of one woman receiving co-treatment with oral contraceptives (arm A). The respective infertility rates and 95% confidence intervals were 90% in arm A (62%-99%) and 100% in arm B (76%-100%). Combining arm A and arm B, the infertility rate in all 19 patients determined by AMH after minimally 12 months was 95% (78%-99%). ConclusionIn this prospectively randomised study in HL patients, no meaningful ovarian protection with hormonal co-treatment during HL therapy consisting of 8 cycles of escalated BEACOPP has been achieved. Though the confidence interval in this study is large due to the limited number of patients, the results do certainly not support the use of oral contraceptives or GnRH analogues to prevent ovarian failure in young women during this intensive chemotherapy regimen. Thus, alternative strategies for the protection of ovarian function should be offered to young women before the start of treatment. Disclosures:Off Label Use: Gonadotropin-releasing hormone agonistic analoges inhibiting follicular growth in the ovary with purpose to reduce infertility.

Rates of Postcancer Parenthood

Rates of Postcancer Parenthood

Ovarian failure following cancer treatment: current management and quality of life

There is a lack of evidence regarding current screening practices for incipient ovarian failure in young women following gonadotoxic therapy and the most appropriate form of estrogen replacement. This study examined the (i) prevalence and management of ovarian failure and (ii) quality-of-life implications of early menopause (EM). A medical case note audit for 288 women with a history of gonadotoxic therapy (aged 18-50 years) was conducted. Self-reported quality-of-life data were obtained from 178 (62%). Ovarian screening was recorded in 44% of medical case notes, and ovarian failure was documented for 35%. From the self-reported data, 89/178 (50%) women reported experiencing an EM/ovarian failure. Worse menopausal symptoms were negatively associated with both sexual activity [pleasure (r = 0.29, P < 0.01), discomfort (r = 0.50, P < 0.001) and habit (r = 0.22, P < 0.05)] and general quality of life (P = 0.01). Hormone replacement therapy is the most commonly prescribed estrogen preparation; however, 34% of women with EM/ovarian failure reported not taking any replacement therapy. Given the extent and impact of menopausal symptoms, further work is needed to establish systems for screening ovarian function and to determine appropriate and effective management of ovarian failure.

Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women

Menopause is associated with increased visceral adiposity and reduced insulin sensitivity. It remains unclear whether these changes are due primarily to ovarian failure or aging. The aim of this study was to clarify the impact of ovarian failure on body composition and insulin sensitivity in young women. In a cross-sectional study, we compared main outcome measures (body mass index, body composition by dual-energy x-ray absorptiometry, and insulin sensitivity by Quantitative Insulin Sensitivity Check Index) in three groups: women with 46,XX premature ovarian failure (POF), women with premature ovarian failure associated with 45,X or Turner syndrome (TS), and normal control women (NC). Participants were enrolled in National Institutes of Health Clinical Center protocols between years 2000 and 2005. Mean body mass index (+/- SD) was lower in women with POF (n = 398): 24.3 +/- 5 kg/m versus 27.8 +/- 7 for women with TS (n = 131) and 26.6 +/- 4 for controls (n = 73) (both P < 0.001). Only 33% of women with POF were overweight or obese, compared with 56% of those with TS and 67% of NC women (P < 0.0001 for both). Despite less obesity, women with POF had lower insulin sensitivity (0.367 +/- 0.03) compared with those with TS (0.378 +/- 0.03, P = 0.003) and NC women (0.376 +/- 0.03, P = 0.04). In groups selected for similar age and body mass index, women with POF (n = 89), women with TS (n = 48), and NC women (n = 40) had similar total body and trunk adiposity. After adjustment for age and truncal adiposity, women with POF had significantly lower insulin sensitivity than women with TS (P = 0.03) and NC women (P = 0.049). In contrast to observations in middle-aged postmenopausal women, ovarian failure in young women is not associated with increased total or central adiposity. In fact, women with TS were similar to NC women, whereas women with POF were leaner. The lower insulin sensitivity observed in women with POF deserves further investigation.

Fertility options in young breast cancer survivors: a review of the literature.

To describe the impact of treatment on fertility, discuss fertility-sparing options available for women with breast cancer, and explore pregnancy subsequent to breast cancer. Published research, clinical articles, book chapters, and abstracts. The risk of amenorrhea associated with alkylating agents in breast cancer survivors is well known. Fertility-sparing options before, during, and after treatment are possible with the use of assistive reproductive technology. Young breast cancer survivors are concerned about stimulating recurrence with subsequent pregnancy, health during pregnancy, and family matters. Current data about the effects of treatment on amenorrhea, subsequent pregnancy after treatment, preservation of ovarian function during adjuvant therapy, and management of ovarian failure in young women with breast cancer are important to include in discussions and counseling. Young women deserve a thoughtful discussion about their concerns among their multidisciplinary team, including oncology nurses, oncologists, and social workers. Effects of treatment on fertility are well known. Women with fertility concerns should be referred to a reproductive endocrinology team at the time of diagnosis rather than after treatment has ended.

O espectro das falências ovarianas ligadas ao cromossomo X

A falência ovariana manifesta-se clinicamente por amenorréia primária ou secundária, e do ponto de vista hormonal caracteriza-se pelos níveis elevados de gonadotrofinas hipofisárias, principalmente FSH, cuja etiologia pode ser atribuída a varias causas, como redução numérica ou rearranjos do cromossomo X, entre outras. Além da síndrome de Turner (monossomia do cromossomo X, com ou sem mosaicismo cromossômico), cujo principal estigma - a baixa estatura - e o infantilismo sexual apontam o diagnóstico, rearranjos do braço longo de X (Xq), ou mutações instaladas em genes mapeados neste cromossomo estão relacionados com a falência ovariana em meninas pré-púberes e em mulheres adultas jovens, sem outros sinais clínicos. Neste cromossomo, nos segmentos da falência ovariana precoce (FOP1 e FOP2) situam-se genes já relacionados à insuficiência ovariana de instalação precoce. Esta revisão trata destas alterações, algumas detectadas pelas técnicas citogenéticas convencionais, outras somente por meio de recursos de biologia molecular

Hypergonadotropic ovarian failure in young women

The purpose of this study is to evaluate 13 patients with primary ovarian failure (POF). All patients were less than 35 years of age. Serum FSH, performed by RIA, was in the post-menopausal range in all patients. Karyotype with Q-banding was performed on peripheral leukocytes and/or ovarian tissue. All patients had 46XX karyotype. Eleven patients had laparoscopy or laparotomy and ovarian biopsy. Two of the 11 patients had ovarian follicles. One patient had Graves' disease. Based on our data, we offer these conclusions. A thorough evaluation of patients with premature ovarian failure is essential. Testing for autoimmune endocrinopathies should be considered in POF patients who exhibit any signs of endocrine dysfunction. A peripheral karyotype with banding should be performed on all patients. The resistant ovary syndrome may occur with greater frequency than has previously been reported and a review of the literature on the resistant ovary syndrome is presented.

Cytotoxic-lnduced Ovarian Failure in Hodgkin's Disease

Chemotheraphy for Hodgkin's disease produces ovarian failure in young women. The consequences of this are emotional distress, sexual dysfunction, and the disruption of families and friendships. These previously unappreciated side effects of cytotoxic therapy had developed in 25 of 41 patients, among whom we conducted a retrospective study.