Decline In Ovarian Reserve Research Articles

Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with "normal" CGG repeat status.

The objective of this analysis is to examine the relationship between Fragile X Mental Retardation 1 gene (FMR1) cytosine-guanine-guanine (CGG) repeat number and ovarian reserve, with a particular focus exclusively on the range of CGG repeat number below the premutation (PM) range (<55 CGG repeats). Our study included female patients who underwent assessment of FMR1 CGG repeat number and serum anti-Mullerian hormone (AMH) in 2009-2014. To examine the association between FMR1 repeat number and serum AMH, we created three summary measures of CGG repeat number for the two alleles-"Sum," "Max," and "Gap" (absolute difference). Using multivariable regression models, controlling for age, we then analyzed the impact of these summary measures on AMH. A total of 566 patients were included in our study. Using multivariable regression models, we found that the relationship between CGG repeat number and AMH differed depending on age. Specifically, in younger women, AMH increased by 7-8 % (Sum p < 0.01, Max p = 0.04) for every 1 unit increase in CGG repeat number. In contrast, starting at age 40, there was a 3 to 5 % decline in AMH for every 1 unit increase in CGG repeat number (Sum p < 0.01, Max p = 0.04). This is the first study to report a statistically significant correlation of ovarian reserve and CGG repeat number in women with <55 CGG repeats. Although these women are generally considered to have a normal phenotype, our data suggest that increasing CGG repeat number within this normal range is associated with a more rapid decline in ovarian reserve.

Abstract P1-09-06: A prospective longitudinal study of the impact of breast cancer treatment with adjuvant chemotherapy or tamoxifen alone on ovarian reserve

Abstract Background: Many women with breast cancer (BC) of reproductive age would prefer to preserve their fertility and ovarian function, if possible. However, available information is insufficient to predict the likelihood and extent of ovarian damage that will be suffered by an individual woman. In prior studies, menses was used as a surrogate for fertility, but it is a poor marker of future fertility. Preliminary work suggests that anti-mullerian hormone (AMH) may be a better surrogate for ovarian reserve. The goal of this study is to delineate the extent of ovarian damage from specific treatment regimens by using serum AMH. Here we report results from the largest longitudinal study with a pretreatment evaluation to measure the impact of both chemotherapy (chemo) and tamoxifen (tam) on ovarian reserve in BC patients. Methods: A multi-institutional longitudinal IRB-approved study was performed in 207 premenopausal women with stage 0-III BC. AMH levels were evaluated at baseline and 1 yr post completion of adjuvant chemo or 1 yr post initiation of tam. After the exclusions (failure to follow-up, sample inadequacy, presumed PCOS and consent withdrawal), 115 women ages 26-46 (median 38) were available for analysis at 1 yr post treatment (primary endpoint). AMH levels were measured in frozen sera with an in-house ultrasensitive ELISA assay and were log transformed due to non-normal distribution. Results were analyzed with Wilcoxon rank sum test and repeated measures ANOVA to adjust for age, tam use and stage. Results: In the 115 evaluable women, 98 pts had HR positive BC &amp; 17 had triple negative BC. 77 pts received anthracycline-based (ddAC-T/EC-T) chemo, 26 non-anthracycline-based chemo (TC/CMF/TH) &amp; 12 tam only. In the 103 women who received chemo, compared to baseline (median 0.21 ng/ml, 0.001-3.9 ng/ml), AMH levels declined significantly (median 0.11 ng/ml, 0.001-4.47 ng/ml; p&amp;lt;0.0001) at 1 yr post chemo. The type of chemo, stage and adjuvant tam use did not significantly impact the results. In the 12 women who received tam only, compared to baseline (median 0.505 ng/ml, 0.010-1.27 ng/ml), AMH levels declined significantly (median 0.155 ng/ml, 0.010-0.91 ng/ml; p=.0049) at 1 yr. Despite a significant decline in ovarian reserve by AMH, 69% (66/95) of pts who received chemo had return of menses by 1 yr post treatment. Conclusion: This longitudinal study shows that BC chemo is detrimental to ovarian reserve. Although a decline in AMH was also seen in pts treated with tam only, this is a small cohort and the results are hypothesis generating. The decline in AMH may be due to ovarian stimulation from tam, which can cause predominance of larger follicles that produce less AMH rather than actual reduction in ovarian reserve. This needs to be studied in a larger cohort. The fact that the majority of pts resumed their menses despite a significant decline in their ovarian reserve by AMH indicates that resumption of menses is not the best measure of ovarian normalcy/fertility. This new info can be used for counseling pts in childbearing ages so they can make better informed decisions on fertility preservation, if desired. Supported by NIH RO1 HD053112, Jodi Spiegel Fisher Cancer Foundation and Susan G. Komen Foundation. Citation Format: Shari B Goldfarb, Giuliano Bedoschi, Eli Grunblatt, Sumanta Goswami, Tessa Cigler, Jessica Quistorff, Fernanda Pacheco, Robert Stobezki, Mark Robson, Fred Moy, Clifford Hudis, Sujata Patil, Maura Dickler, Kutluk Oktay. A prospective longitudinal study of the impact of breast cancer treatment with adjuvant chemotherapy or tamoxifen alone on ovarian reserve [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-09-06.

Effect of hemostatic method on ovarian reserve following laparoscopic endometrioma excision; comparison of suture, hemostatic sealant, and bipolar dessication. A systematic review and meta-analysis.

We reviewed the literature to determine whether different hemostatic methods used following laparoscopic endometrioma excision have differing effects on ovarian reserve. We performed a systematic literature search using the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and Ovid MEDLINE In-Process & Other Non-Indexed Citations databases to identify studies comparing the rate of change in levels of serum anti-Müllerian hormone (AMH) at 3months after laparoscopic endometrioma excision using bipolar dessication (BD) or suturing/application of a hemostatic sealant (HS) for hemostasis. Abstracts of the annual meetings of the American Society of Reproductive Medicine, the European Society of Human Reproduction and Embryology, and the American Association of Gynecological Laparoscopists were searched as well. A total of 712 articles were identified, of which 6 were included in the qualitative analysis. Four studies involving 213 women were included in the meta-analysis. Our qualitative analysis suggested that BD is more detrimental to ovarian reserve than alternative hemostatic methods. There is moderate-quality evidence favoring HS and low-quality evidence favoring sutures over BD. The meta-analysis also showed that alternative hemostatic methods are associated with significantly less decline in ovarian reserve compared with BD. The mean decline in serum AMH levels was 6.95% less with alternative hemostatic methods than with BD (95% CI, -13.0% to -0.9%; p=.02) at 3months after surgery. According to the best available evidence, the use of BD should be cautiously limited, even avoided when possible, during endometrioma excision in women who desire to have children.

The impact of endometrioma and laparoscopic cystectomy on ovarian reserve and the exploration of related factors assessed by serum anti-Mullerian hormone: a prospective cohort study.

BackgroundTo evaluate the impact of the presence of endometrioma and laparoscopic cystectomy on ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) level. In addition, factors related to the decline in ovarian reserve were analyzed.MethodsFrom June 2013 to January 2014, we prospectively included 40 women with endometriomas as the study group (group A), 36 women with tubal factor infertilities as control group 1 (group B) and 22 women with the other benign ovarian cysts as control group 2 (group C). The women with ovarian cysts underwent laparoscopic cystectomy. Serum AMH levels were determined preoperatively and at 1 month after surgery.ResultsThe endometrioma group had lower AMH levels (1.53 ± 1.37 ng/ml) compared with the other benign ovarian cyst group (2.20 ± 1.23 ng/ml) and the tubal factor infertility group (2.82 ± 1.74 ng/ml). The rate of serum AMH decline 1 month after surgery in the endometrioma group (0.62 ± 0.35) was larger than the decline in the other benign ovarian cyst group (0.32 ± 0.30). The preoperative AMH level showed a significant correlation with patient age (group A, r = −0.32; group B, r = −0.54; group C, r = −0.71); there was a statistically significant correlation between the rate of serum AMH decline and endometrioma diameter as well as with the preoperative serum AMH level. In addition, the rate of serum AMH decline was larger for bilateral endometriomas than for unilateral endometriomas, but there was no similar correlation in the other benign ovarian cyst group. The rate of AMH decline after surgery in the subgroup of >7 cm was significantly higher than in the subgroup of ≤7 cm.ConclusionsOvarian endometriomas per se may damage ovarian reserve, and cystectomy of endometriomas may cause greater damage to ovarian reserve compared with other benign ovarian cysts. The operation-related damage to the ovarian reserve was positively related to whether the endometriomas were bilateral, as well as cyst size (especially for cysts >7 cm), but was negatively related to the preoperative serum AMH level. Age was a negative factor that affected the ovarian reserve.

Female reproductive decline is determined by remaining ovarian reserve and age.

The early decline and loss of female fertility in humans and other species represents an evolutionary paradox. Despite being born with a vast stock of oocytes, females encounter an exhaustion of ovarian reserve and sterility half way through their natural lives. Female reproductive ageing has been proposed to proceed as an ongoing decline in ovarian reserve, determined by remaining ovarian follicle number. However, despite extensive modelling, the respective contributions of intra-, inter-, and extra-ovarian signalling have not been fully characterised. It remains unclear whether reproductive ageing progresses simply as a pre-determined function of remaining ovarian follicles, or as an age-dependent process in humans. Here, we have analysed ovarian response to hormonal stimulation in women who have undergone surgical removal of a single ovary, in order to investigate the relative contributions of intra-, inter, and extra-ovarian signalling on reproductive ageing. Our data show that in unilaterally oophorectomised women, ovarian response to follicle stimulating hormone (FSH) declines beyond levels predicted by a total ovarian follicle pool model of reproductive ageing. Maintenance of ovarian function later in reproductive life, despite the removal of half of the total ovarian reserve, suggests a role for an extra-ovarian age-dependent regulation of reproductive decline. This highlights the need for further work to identify signalling factors that communicate age-related signals between the soma and the germline.

Reference values in ovarian response to controlled ovarian stimulation throughout the reproductive period

The age-related decline in ovarian response to gonadotropins has been well known since the beginning of ovarian stimulation in IVF cycles and has been considered secondary to the age-related decline in ovarian reserve. The objective of this study was to establish reference values and to construct nomograms of ovarian response for any specific age to gonadotropins in IVF/ICSI cycles. We analyzed our database containing information on IVF cycles. According to inclusion and exclusion criteria, a total of 703 patients were selected. Among inclusion criteria, there were regular menstrual cycle, treatment with a long GnRH agonist protocol and starting follicle-stimulating hormone (FSH) dose of at least 200 IU per day. To estimate the reference values of ovarian response, the CG-LMS method was used. A linear decline in the parameters of ovarian response with age was observed: the median number of oocytes decreases approximately by one every three years, and the median number of follicles >16 mm by one every eight years. The number of oocytes and growing follicles corresponding to the 5th, 25th, 50th, 75th and 95th centiles has been calculated. This study confirmed the well known negative relationship between ovarian response to FSH and female ageing and permitted the construction of nomograms of ovarian response.

The gonadal effects of diabetes

The functional reproductive alterations seen in women with type 1 diabetes (T1D) have changed as therapy has improved. Historically, patients with T1D and insufficient metabolic control exhibited a high prevalence of amenorrhea, hypogonadism, and infertility. Recent publications have shown that in spite of intensive insulin therapy, some delay in the age of thelarche, pubarche and menarche is still observed in girls with T1D. In addition, ovarian hyperandrogenism may be observed during late adolescence and an increased prevalence of hirsutism and polycystic ovarian syndrome (PCOS) has been described in adult women with T1D. These endocrine abnormalities may be related to non-physiologic insulin replacement therapy and to hyperglycemia. Insulin is well known for its effects on carbohydrate metabolism, but this hormone also plays an important role in regulating ovarian function. Granulosa, theca and stromal ovarian cells may be affected by insulin deficiency or excess, which may be present in women with type 1 diabetes mellitus (T1D)[1]. Diabetes disrupts hypothalamic-pituitary-ovarian function, as documented by animal model studies which have helped to decipher the underlying basis of these conditions and have highlighted the variable contributions of defective leptin, insulin and kisspeptin signalling to the mechanisms of perturbed reproduction in T1D[2]. Effects of diabetes on gonadal function vary according to the age of the patient. Young girls during adrenarche exhibit an elevation of DHEAS, androstenedione, inhibin B and anti-mullerian hormone[3], an endocrine profile that is similar to the one observed in young girls in risk of developing polycystic ovarian syndrome later in life. During puberty a delay in pubertal development has been described which is followed by menstrual irregularities and hyperandrogenism during adolescence [1,4,5]. Despite these abnormalities in ovarian function, ovulatory functions is preserved in adolescents with type 1 diabetes[6]. Later in life, adult women with type 1 diabetes exhibit PCOS, polycystic ovaries at the ultrasonographic exam, menstrual irregularities and early decline in ovarian reserve[7-9]. Clearly, despite improvements in insulin therapy, T1D patients still suffer several significant clinical problems, such as pubertal delay, menstrual disturbances and hyperandrogenism which may ultimately lead to the development of PCOS in adulthood. (Fondecyt 1100123 y 1050452)

Prospective assessment of the impact of endometriomas and their removal on ovarian reserve and determinants of the rate of decline in ovarian reserve

Do the presence of endometriomas and their laparoscopic excision lead to a decrease in ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) levels? Both the presence and excision of endometriomas cause a significant decrease in serum AMH levels, which is sustained 6 months after surgery. No previous comparison of serum AMH levels between women with and without endometrioma has been reported. However, studies have suggested a decline in serum AMH levels 1-3 months after endometrioma excision but long-term data are needed. A prospective cohort study including 30 women with endometrioma >2 cm were age matched with 30 healthy women without ovarian cysts. Women with endometrioma underwent laparoscopic excision with the stripping technique. Serum AMH level and antral follicle count (AFC) were determined preoperatively, 1 and 6 months after surgery. Correlation analyses were undertaken in order to identify determinants of surgery-related change in ovarian reserve. Compared with controls at baseline, women with endometrioma had lower AMH levels (4.2 ± 2.3 versus 2.8 ± 2.2 ng/ml, respectively, P = 0.02) and AFC (14.7 ± 4.1 versus 9.7 ± 4.8, respectively, P < 0.01). Serum AMH levels were further decreased 6 months after surgery (2.8 ± 2.2 versus 1.8 ± 1.3 ng/ml, P = 0.02), while AFC remained unchanged (9.7 ± 4.8 versus 10.4 ± 4.2, P = 0.63). The rate of decline in AMH was not correlated with age, laterality of endometrioma, cyst diameter or the number of primordial follicles on the surgical specimens. The preoperative serum AMH level was positively correlated with the rate of decline in serum AMH after surgery (r = 0.47, P = 0.02). The absence of a non-treated group of women with endometriomas as a further control prevents comment on the presence of a progressive decline in ovarian reserve related to endometrioma per se. The sample size may be too small for detection of factors correlated with the extent of ovarian damage. While the findings are mostly in agreement with previous studies, the present study is the first to show that the presence of endometrioma per se is associated with a decrease in ovarian reserve. The extent of surgery-related decline in ovarian reserve is not predictable using preoperative or perioperative factors. It may be prudent to measure AMH levels preoperatively and delay/avoid surgical excision as far as is possible if subsequent fertility is a concern. Additional studies are required to further investigate whether the endometrioma-related decline in ovarian reserve per se is progressive in nature and whether it exceeds the surgery-related decline. This study was funded by the Research Fund of the Uludag University School of Medicine. The authors have no conflict of interest associated with this study.

S3 Polar body biopsy and array CGH for aneuploidy in advanced maternal age

Aneuploidy testing has started in the 1990s and still to date it is a topic which is controversial and can provoke vivid discussions especially if it comes to the question if such an approach is beneficial in assisted reproduction. Among the different techniques which are applied in routine since then, biopsy of polar bodies at the oocyte/zygote stage and biopsy of trophectoderm cells at the blastocyst stage are those which are at present in the focus of interest. Both techniques seem to have the highest potential if combined with a diagnostic approach which allows investigating all chromosomes. One such approach is comparative genomic hybridization (CGH). Over the last decade CGH has made substantial progression from the conventional chromosome-based hybridisation template to the first CGH-arrays and to the latest single channel array format of today. If the focus is on maternal aneuploidies which have manifested during the meiotic progression of the developing oocyte, polar body biopsy and array-CGH is an option for investigating chromosomal aberrations without touching the embryo and this strategy clearly avoids the problem of embryo mosaicism. For some patients this approach is ethically better acceptable. Retrieval of polar bodies can be done either sequential or simultaneously, provided that the timing is adapted to the course of meiosis (for biopsy) and to the integrity of the chromosomal content of the polar bodies (for amplification). Several publications have reported on the use of this technology for the investigation of structural as well as numerical chromosome aberrations. In patients with advanced maternal age the results of these studies show that at an average maternal age of 40 the mean rate of aneuploidy is 70%, meaning that out of 10 oocytes 3 are chromosomally intact and suitable for transfer. As there is a decline in ovarian reserve in women with advanced age, the rate of cancelled transfers due to the presence of only aneuploid oocytes is very high among these women. To date there is no systematic study available which clearly states to what extent polar body biopsy and array-CGH benefits assisted reproduction treatment. The main question is if aneuploidy testing in advanced maternal age leads to lower abortion rates and/or if it does support higher take home baby rates. Following a pilot study on polar body biopsy and arrayCGH, a multicentre trial has been initiated by the European Society for Human Reproduction and Embryology (ESHRE) which aims to clarify this point in the near future.

An assessment of female university students’ attitudes toward screening technologies for ovarian reserve

To assess female university students' attitudes toward screening technologies for ovarian reserve and their potential influence on career and family planning decisions. Online survey. Not applicable. Respondents from 4 universities in Northern California. None. Proportion with interest in screening technologies for ovarian reserve. Of the 328 respondents, 79% were interested in learning about the current status of their ovarian reserve. Hypothetically, if informed that ovarian reserve was very low, 53% would consider oocyte cryopreservation (even when informed that it is experimental); however, only 29% would consider stopping educational or professional pursuits to focus on conceiving. Participants also demonstrated gaps in knowledge, believing that the decline in ovarian reserve starts later than it actually does, that diet and nutrition can preserve ovarian reserve, and that infertility treatments are highly effective regardless of how severe the depletion of the egg supply is. Women attending universities are interested in assessing their own ovarian reserve. Gaps in knowledge about ovarian reserve exist among these reproductive-aged women.

External validation of nomogram for the decline in serum anti-Müllerian hormone in women: a population study of 15,834 infertility patients

The value of anti-müllerian hormone (AMH) as a marker of the ovarian reserve is becoming clear in a range of clinical contexts. This study reports the external validation of a quadratic model-based AMH–age nomogram using a cohort of 15,834 US women. All models previously investigated for the decline in ovarian reserve (i.e. linear, bi-linear, decay curve, power and quadratic models) tended to overestimate AMH by approximately 11% versus the published nomogram, indicating some between-population heterogeneity. Bootstrapping of 1000 datasets indicated that the quadratic model provided the best fit, confirming the choice of this model in the AMH–age nomogram. This nomogram can therefore be used with confidence for the interpretation of AMH in clinical populations.

112 THROMBOPHILIA WORK-UP IN WOMEN WITH RECURRENT IVF FAILURE

Mullerian inhibiting substance regulates the development of early preantral and small antral follicles and acts as an inhibitor of the FSH sensitivity of growing antral follicles, which then serves to negatively modulate the FSH-dependent selection of dominant follicles. The highest values of MIS in women are attained after puberty and subsequently decrease with age, likely reflecting the agerelated decline in ovarian reserve. A number of investigators presented data to support the hypothesis that MIS could be used as a biomarker of ovarian age and ovarian reserve in humans. In humans, findings showed that serum MIS levels decline with increasing reproductive age, that after oophorectomy there is a precipitate drop in levels of MIS, that after gonadotropin stimulation for assisted reproductive technologies, the levels of MIS decline, and that the follicularfluid MIS levels differ between younger patients and older patients. Kevenaar et al. measured serum MIS in mice, and the decline in MIS levels found in aging mice is consistent with the results obtained in humans. A recent study in the Middle East presented by El-Gindi and colleagues showed a strong association between midluteal, early follicular, ovulatory AMH levels and number of oocyte retrieved from a thirty three women undergoing their first ICSI cycle after ovulation superstimulation with long protocol. Midluteal and early follicular AMH may offer good prognostic value for clinical pregnancy.

Does the ovarian reserve decrease from repeated ovulation stimulations?

The majority of infertility patients require more than one in-vitro fertilization cycles to achieve pregnancy, which results in repeated stimulation in the ovaries. There have been raising concerns for patients about the effect of repetitive assisted reproductive technology (ART) cycles on ovarian response in subsequent cycles. Whether or not there is deterioration in ovarian response with repetitive treatment will allow clinicians to provide better counseling to patients before treatment. The single determinant factor that has been shown in affecting ovarian reserve for patients undergoing repeated ART cycles is age. Current evidence has suggested that repetitive ovarian stimulation cycles with intrauterine insemination can be performed without clinically impairing ovarian response. Oocyte donors can be invited for at least three cycles without a negative effect on ovarian response to gonadotropins, number of mature oocytes retrieved, embryo quality, or pregnancy rates. There are limited available published data on this topic. Research studies have shown that there is no detrimental effect on ovarian function of egg donors who undergo repetitive ovarian hyperstimulation. Overall findings also show that there is no significant decline in ovarian reserve in patients who undergo up to three repeated in-vitro fertilization cycles. For patients undertaking more than three cycles, the results become equivocal because age becomes a determinant factor with both pregnancy and live birth rate declining with repetitive cycles.

Long-term effects of uterine fibroid embolization on ovarian reserve: a prospective cohort study

To determine whether uterine fibroid embolization may advance ovarian follicular depletion in reproductive-aged women with apparently normal baseline ovarian function. Prospective cohort study. University tertiary care center. Thirty-six patients aged 26 to 39 years with fibroids, regular menstrual cycles, and day 3 serum FSH levels<10 mIU/mL and 36 matched control women. Day 3 serum FSH and E2 levels and ultrasound-based antral follicle count and ovarian volume were determined before (baseline) and at 12, 24, 36, 48, and 60 months after embolization and compared with those of the control group. Menstrual status was determined annually on the basis of prospectively recorded menstrual calendars. Longitudinal changes in hormone levels, ultrasound measures, and bleeding patterns. Although the FSH and E2 levels increased significantly and the antral follicle count and ovarian volume values declined significantly over time within the groups, no significant differences were found between the groups. The cycle remained regular in all but two women (one in the embolization group and one in the control group), who started having cycle irregularity after 24 months and 36 months follow-up, respectively. This long-term follow-up study suggests that fibroid embolization does not lead to an accelerated decline in ovarian reserve in younger patients.

Early prenatal androgenization results in diminished ovarian reserve in adult female rhesus monkeys

Early prenatal androgenization (PA) accelerates follicle differentiation and impairs embryogenesis in adult female rhesus monkeys (Macaca mulatta) undergoing FSH therapy for IVF. To determine whether androgen excess in utero affects follicle development over time, this study examines whether PA exposure, beginning at gestational days 40-44 (early treated) or 100-115 (late treated), alters the decline in serum anti-Mullerian hormone (AMH) levels with age in adult female rhesus monkeys and perturbs their ovarian response to recombinant human FSH (rhFSH) therapy for IVF. Thirteen normal (control), 11 early-treated and 6 late-treated PA adult female monkeys had serum AMH levels measured at random times of the menstrual cycle or anovulatory period. Using some of the same animals, basal serum AMH, gonadotrophins and steroids were also measured in six normal, five early-treated and three late-treated PA female monkeys undergoing FSH therapy for IVF during late-reproductive life (>17 years); serum AMH also was measured on day of HCG administration and at oocyte retrieval. Serum AMH levels in early-treated PA females declined with age to levels that were significantly lower than those of normal (P < or = 0.05) and late-treated PA females (P < or = 0.025) by late-reproductive life. Serum AMH levels positively predicted numbers of total/mature oocytes retrieved, with early-treated PA females having the lowest serum AMH levels, fewest oocytes retrieved and lowest percentage of females with fertilized oocytes that cleaved. Based on these animals, early PA appears to program an exaggerated decline in ovarian reserve with age, suggesting that epigenetically induced hormonal factors during fetal development may influence the cohort size of ovarian follicles after birth.

Antimullerian hormone, but not follicle stimulating hormone, reflects decline in ovarian reserve associated with oral cyclophosphamide use in Wegener's granulomatosis for the WGET research group

OBJECTIVE: Our aim was to determine the effect of cyclophosphamide (CYC) on ovarian reserve markers antimullerian hormone (AMH) and follicle stimulating hormone (FSH) in patients with Wegener's Granulomatosis (WG). DESIGN: Case control study of stored plasma. MATERIALS AND METHODS: Patients in Wegener's Granulomatosis Etanercept Trial (WGET) received cyclophosphamide (CYC) for severe WG and methotrexate for limited WG. The first and last available plasma samples from the 42 women who were under age 50 at WGET enrollment were analyzed in duplicate for FSH (ELISA Calbiotech) and AMH (ELISA DSLabs). Linear regression analysis and Wilcoxon rank sum tests were performed. RESULTS: While the change in AMH during the study was closely correlated with the dose of CYC received (0.8 ng/mL decline per 10 gms CYC, p=0.009), change in FSH did not correlate with CYC dose. Furthermore, AMH, but not FSH, exhibited a significant decline in patients receiving CYC compared to no CYC.Table 1Change in AMH & FSH from baseline to end of study.CYC in WGETNo CYC in WGETParameterNMean ± std.NMean ± std.p-valueRaw Change of AMH (last visit - baseline)∗Baseline AMH<0.5 ng/mL excluded.11-2.15 ± 1.9460.36 ± 0.890.011Raw Change of FSH (last visit - baseline)†Oral contraceptive pill & GnRH agonist users excluded.227.40 ± 18.4410-1.73 ± 14.080.347∗ Baseline AMH<0.5 ng/mL excluded.† Oral contraceptive pill & GnRH agonist users excluded. Open table in a new tab CONCLUSIONS: In this study, AMH was more closely linked to CYC ovarian damage than FSH. FSH testing was not obtained in the early follicular phase, so was influenced by endogenous estradiol and progesterone during the ovarian cycle of ovulating women. In the oncofertility setting, where patients are not routinely seen in the early follicular phase and may be taking oral contraceptives, AMH is a superior marker of ovarian function.

Anti-mullerian hormone as predictor for ovarian reserve is associated with age at menopause in Fragile X premutation carriers

OBJECTIVE: Carriers of a premutation (repeat length 59-200) in the Fragile X mental retardation (FMR1) gene are known to be at risk for primary ovarian insufficiency (FXPOI). We investigated whether FXPOI is due to low ovarian reserve and/or accelerated decline of ovarian reserve. In addition, we addressed the question whether the levels of anti-Müllerian hormone (AMH) can predict the age at which menopause occurred. DESIGN: Retrospective controlled cohort study. MATERIALS AND METHODS: We determined AMH and follicle stimulating hormone (FSH) levels in blood samples with a 10 year interval (T1 and T2) in 101 women from 46 families with Fragile X syndrome. The levels of premutation carriers (PC) were compared to those of women with a normal repeat length or a full mutation. At T2 40 women were postmenopausal, with time intervals between AMH sample and final menstrual period (FMP) ranging from a few months to 10 years. Statistical multilevel analyses were performed using linear mixed models correcting for age, taking within family and within subject correlations into account. RESULTS: Premutation carriers (n=41) had significantly lower AMH levels (median AMH at T1 for PCs 0.21 ng/ml versus 1.27 ng/ml for control group (n=60), p=0.001), but showed an equal decline in AMH levels (PCs -62.5% versus control group -74.8%) over 10 years (p=0.13). FSH levels were higher (median FSH at T1 for PCs 12.3 IU/l versus control group 8.8 IU/l), but were not elevated (>10 IU/l) until above 40 years of age. Within 7 years until FMP, AMH levels were low and ranged from undetectable (<0.10 ng/ml) to 0.38 ng/ml, while FSH levels ranged from normal (<10 IU/l) to postmenopausal height (>40 IU/l). CONCLUSIONS: Fragile X premutation carriers demonstrate a similar decline in ovarian reserve as women without a risk of diminished ovarian reserve. Therefore, FXPOI may be associated with a predisposition to lower ovarian reserve. AMH levels may serve as a predictor of time until menopause (p=0.048) and, thus, may be useful at an early age.

The FMR1 gene, a regulator of functional ovarian reserve over reproductive life times

OBJECTIVE: 26-32 triple CGG repeats on the FMR1 gene represent normal, while < 26 and >32 repeats increase risk for early decline in ovarian reserve. Effects should, however, vary depending on whether both alleles are in normal (norm) range or either 1 [heterozygous (het) ] or 2 [homozygous (hom) ] are abnormal.

MATERNAL EXPOSURE TO SECOND-HAND SMOKE AND SUPER OVULATION OUTCOME FOR ASSISTED REPRODUCTION

Background The effect of smoking cigarettes is followed by diverse effects on ovaries and developing follicles but the effect of passive smoking on ovarian function is unknown. On the other hand, the ovarian response to induction is a very important step in assisted reproduction. The aim of this study is to compare ovarian response in passive smokers and non-passive smokers in an assisted reproductive program. Materials and methods In a cohort study at the Isfahan Fertility and Infertility Center, there were 72 women in the passive smoker group and 72 women in the non-passive smoker group who underwent an assisted reproductive technology (ART) program. The follicle number at administration of human chorionic gonadotropin (HCG), number of gonadotropin ampoules and duration of super ovulation induction were compared. Results Statistical analyses indicated that the number of mature follicles in the passive smoker group was not different from the control group; but the number of unresponsive cycles to super ovulation in the passive smoker group (33.3%) was significantly higher than the control group (12.5%). Duration of induction and number of gonadotropin ampoules were not different between the two groups Conclusion The results of this study show that exposure to second-hand smoke increases the chance of unresponsiveness to ovulation induction. This condition may be due to the result of decline in ovarian reserve in second-hand smokers. The duration of induction and number of gonadotropin ampules is similar in the two groups. Furthermore, the results show that exposure to cigarette smoke does not clinically impact women with good ovarian reserve.

Elevated serum müllerian-inhibiting substance may be a marker for ovarian hyperstimulation syndrome in normal women undergoing in vitro fertilization

We identified patients who experienced ovarian hyperstimulation syndrome (OHSS) (n = 16) and compared their baseline pretreatment levels of müllerian-inhibiting substance (MIS) to age- and weight-matched patients with normal responses to gonadotropins (n = 14). Baseline serum MIS in patients with OHSS were sixfold higher than those seen in normal controls (3.62 +/- 0.87 vs. 0.63 +/- 0.09 ng/mL; P=.0036), indicating that MIS could potentially serve as a useful marker for identifying patients at risk for OHSS.