Andrea Weghofer

Anti-Müllerian hormone (AMH) defines, independent of age, low versus good live-birth chances in women with severely diminished ovarian reserve.

Maximal receiver operating characteristic curve inflections, which differentiate between better and poorer delivery chances in women with diminished ovarian reserve (DOR) independent of age, were at anti-Müllerian hormone (AMH) 1.05 ng/mL (improved odds for live birth 4.6 [2.3-9.1), 95% confidence interval; Wald 18.8, df = 1], although live births occurred even with undetectable AMH. Pregnancy wastage was very low at AMH ≤0.04 ng/mL but significantly increased at AMH 0.41-1.05 ng/mL, resulting in similarly low live-birth rates at all AMH levels ≤1.05 ng/mL and significantly improved live-birth rates at AMH ≥1.06 ng/mL.

Defining ovarian reserve to better understand ovarian aging

Though a widely utilized term and clinical concept, ovarian reserve (OR) has been only inadequately defined. Based on Medline and PubMed searches we here define OR in its various components, review genetic control of OR, with special emphasis on the FMR1 gene, and discuss whether diminished OR (DOR) is treatable. What is generally referred to as OR reflects only a small portion of total OR (TOR), a pool of growing (recruited) follicles (GFs) at different stages of maturation. Functional OR (FOR) depends on size of the follicle pool at menarche and the follicle recruitment rate. Both vary between individuals and, at least partially, are under genetic control. The FMR1 gene plays a role in defining FOR at all ages. Infertility treatments have in the past almost exclusively only centered on the last two weeks of folliculogenesis, the gonadotropin-sensitive phase. Expansions of treatments into earlier stages of maturation will offer opportunity to significantly improve ovarian stimulation protocols, especially in women with DOR. Dehydroepiandrosterone (DHEA) may represent a first such intervention. Data generated in DHEA-supplemented women, indeed, suggest a new ovarian aging concept, based on aging of ovarian environments and not, as currently is believed, aging oocytes.

The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment?

BackgroundEffects of androgens on follicle maturation have been controversial for some time. Here, we review the potential of their applications in improving human ovulation induction, based on human and animal data, reported in the literature.MethodsWe reviewed the published literature for the years 2005-2011, using relevant key words, in PubMed, Medline and Cochrane reviews, and then performed secondary reviews of referenced articles, which previously had not been known or preceded the searched time period. A total of 217 publications were reviewed.ResultsContrary to widely held opinion, recent data, mostly developed in the mouse, convincingly demonstrate essential contribution of androgens to normal follicle maturation and, therefore, female fertility. Androgens appear most engaged at preantral and antral stages, primarily affect granulosa cells, and exert effects via androgen receptors (AR) through transcriptional regulation but also in non-genomic ways, with ligand-activated AR modulating follicle stimulating hormone (FSH) activity in granulosa cells. While some androgens, like testosterone (T) and dehydroepiandrosterone (DHEA), appear effective in improving functional ovarian reserve (FOR) in women with diminished ovarian reserve (DOR), others may even exert opposite effects. Such differences in androgens may, at least partially, reflect different levels of agonism to AR.DiscussionSelective androgens appear capable of improving early stages of folliculogenesis. They, therefore, may represent forerunners of a completely new class of ovulation-inducing medications, which, in contrast to gonadotropins, affect follicle maturation at much earlier stages.

Comparing anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) as predictors of ovarian function

We compared predictive values of anti-Müllerian hormone (AMH) and baseline FSH with respect to IVF cycle outcomes based on oocyte numbers retrieved and number of clinical pregnancies established. In 76 IVF cycles investigated, AMH was clearly superior in predicting IVF outcomes in comparison with FSH.

Age-specific levels for basal follicle-stimulating hormone assessment of ovarian function.

OBJECTIVE: Traditionally, the most important measurement in the assessment of ovarian function has been age-independent baseline follicle-stimulating hormone (FSH) levels. The objective of this study was to characterize the continuum of ovarian function based on age-specific categories of baseline FSH. METHODS: In a cross-sectional historical cohort study we evaluated records of 434 patients with baseline FSH levels of less than 12 milli international units/mL that underwent ovulation induction for in vitro fertilization (IVF) with long gonadotropin-releasing hormone (GnRH) antagonist or GnRH agonist suppression and modal gonadotropin stimulation of 300 units of gonadotropins per day. In these patients with apparent normal ovarian function by current baseline FSH criteria and with routine ovarian stimulation, we assessed IVF cycle outcomes, including oocyte yields, based on age-specific baseline FSH levels, defined as levels less than or equal to the 95% confidence interval for each age group. RESULTS: Age-specific baseline FSH levels predicted the retrieval of fewer than or equal to four oocytes, with a positive predictive value of 19.5% and a negative predictive value of 88%. The Mantel-Haenszel common odds ratio for fewer than or equal to 4 oocyte production in the presence of premature ovarian aging was 2.8 (95% confidence interval 1.52–5.17; P<.001). CONCLUSION: These results suggest that, within generally accepted normal baseline FSH values, women with baseline FSH above the 95% confidence limits for age produce fewer oocytes in response to normal ovulation induction protocols compared with other women their age. LEVEL OF EVIDENCE: II

Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study

BackgroundDehydroepinadrosterone (DHEA) supplementation improves pregnancy chances in women with diminished ovarian reserve (DOR), by possibly reducing aneuploidy. Since a large majority of spontaneous miscarriages are associated with aneuploidy, one can speculate that DHEA supplementation may also reduce miscarriage rates.MethodsWe retroactively compared, utilizing two independent statistical models, miscarriage rates in 73 DHEA supplemented pregnancies at two independent North American infertility centers, age-stratified, to miscarriages reported in a national U.S. in vitro fertilization (IVF) data base.ResultsAfter DHEA supplementation the miscarriage rate at both centers was 15.1% (15.0% and 15.2%, respectively). For DHEA supplementation Mantel-Hänszel common odds ratio (and 95% confidence interval), stratified by age, was significantly lower, relative to odds of miscarriage in the general IVF control population [0.49 (0.25-0.94; p = 0.04)]. Miscarriage rates after DHEA were significantly lower at all ages but most pronounced above age 35 years.DiscussionSince DOR patients in the literature are reported to experience significantly higher miscarriage rates than average IVF patients, the here observed reduction in miscarriages after DHEA supplementation exceeds, however, all expectations. Miscarriage rates after DHEA not only were lower than in an average national IVF population but were comparable to rates reported in normally fertile populations. Low miscarriage rates, comparable to those of normal fertile women, are statistically impossible to achieve in DOR patients without assumption of a DHEA effect on embryo ploidy. Beyond further investigations in infertile populations, these data, therefore, also suggest the investigations of pre-conception DHEA supplementation in normal fertile populations above age 35 years.

Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation

Dehydroepiandrosterone (DHEA) has been reported to improve oocyte/embryo yields and oocyte/embryo quality in women with diminished ovarian reserve. Whether DHEA objectively improves ovarian reserve is, however, unknown. This study investigated 120 consecutive patients with diminished ovarian reserve, supplemented for 30-120 days (mean 73+/-27) with DHEA (25mg three times daily). Anti-Müllerian hormone (AMH) concentrations were determined in relationship to DHEA supplementation using linear regression and, longitudinally, by examining interaction between days of DHEA treatment and pregnancy success in respect to changes in AMH. AMH concentrations significantly improved after DHEA supplementation over time (P=0.002). Women under age 38 years demonstrated higher AMH concentrations and improved AMH concentrations more than older females. AMH improved longitudinally by approximately 60% (P<0.0002). Women reaching IVF experienced a 23.64% clinical pregnancy rate and conceiving women showed significantly improved AMH concentrations compared with those who did not (P=0.001). DHEA supplementation, thus, significantly improved ovarian reserve in parallel with longer DHEA use and was more pronounced in younger women.

Relevance of triple CGG repeats in the FMR1 gene to ovarian reserve

Most individuals demonstrate 29-30 CGG triple repeats on the FMR1 gene. This may functionally represent a normal range in regard to ovarian reserve. Higher counts reflect risk towards premature ovarian senescence, but lower counts have not been investigated before and, therefore, were the principal subject of this investigation. Amongst 316 consecutive infertility patients, 94 demonstrated <28 repeats (group A), 163 28-33 repeats (group B, considered normal repeat numbers) and 59 > or =34 repeats (group C). The three groups did not differ in age, FSH or anti-Müllerian hormone (AMH) concentrations. Neither FSH nor AMH correlated in linear regression with <28 CGG repeats. In logistic regression, AMH of < or =0.8 ng/ml (indicative of diminished ovarian reserve at all ages) was, however, significantly associated with number of repeats (P < 0.001). Every decrease by five CGG repeats in group A increased the likelihood of diminished ovarian reserve by 40%, while every increase by five CGG repeats in group C increased risk by 50% (both P < 0.002). AMH of < or =0.8 ng/ml statistically correlated overall with decreasing triple CGG repeats throughout all ranges (P < 0.001). Approximately 29-30 CGG repeats appear reflective of normal ovarian reserve, with higher and lower counts denoting similar risks towards premature ovarian senescence.

Live birth chances in women with extremely low-serum anti-Mullerian hormone levels

BACKGROUND To determine whether women with extremely low-serum anti-Mullerian hormone (AMH) levels (<0.1-0.4 ng/ml) still demonstrate live birth potential with assisted reproduction and whether such potential is age dependent. METHODS Between January 2006 and October 2009, 128 consecutive infertility patients with AMH ≤0.4 ng/ml were retrospectively evaluated for pregnancy chances and live birth rates after IVF. RESULTS Patients presented at a mean (±SD) age of 40.8 ± 4.1 years, with mean (±SD) baseline FSH of 15.7 ± 11.1 mIU/ml and mean (±SD) AMH of 0.2 ± 0.1 ng/ml. One hundred and twenty-eight women underwent a total of 254 IVF cycles. Twenty clinical pregnancies were recorded (7.9% per cycle start [95% confidence interval (CI): 4.9-11.9%]; 15.6% cumulative [CI: 9.8-23.1%]). These pregnancies resulted in 13 live births in 12 women (i.e. 11 singletons and a pair of twins) and 8 patients miscarried. Eight deliveries occurred after the first cycle (6.3% per cycle start) and four after subsequent IVF cycles (3.2%). When evaluated according to female age, 70 women ≤42 years presented with 16 clinical pregnancies that resulted in 10 deliveries (14.3%), while 58 patients >42 years presented with four clinical pregnancies that resulted in 2 deliveries (3.4%), representing a reduced pregnancy chance (P = 0.013) and delivery rate (P = 0.036) versus age ≤42 years. CONCLUSIONS With extremely low-serum AMH levels, moderate, but reasonable pregnancy and live birth rates are still possible. Extremely low AMH levels do not seem to represent an appropriate marker for withholding fertility treatment.

Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS)

BackgroundDehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR), and to reduce miscarriage rates by 50-80%. Such an effect is mathematically inconceivable without beneficial effects on embryo ploidy. This study, therefore, assesses effects of DHEA on embryo aneuploidy.MethodsIn a 1:2, matched case control study 22 consecutive women with DOR, supplemented with DHEA, underwent preimplantation genetic screening (PGS) of embryos during in vitro fertilization (IVF) cycles. Each was matched by patient age and time period of IVF with two control IVF cycles without DHEA supplementation (n = 44). PGS was performed for chromosomes X, Y, 13, 16, 18, 21 and 22, and involved determination of numbers and percentages of aneuploid embryos.ResultsDHEA supplementation to a significant degree reduced number (P = 0.029) and percentages (P < 0.001) of aneuploid embryos, adjusted for relevant covariates. Short term supplementation (4-12 weeks) resulted in greatest reduction in aneuploidy (21.6%, 95% CI -2.871-46.031).DiscussionBeneficial DHEA effects on DOR patients, at least partially, are the likely consequence of lower embryo aneuploidy. DHEA supplementation also deserves investigation in older fertile women, attempting to conceive, where a similar effect, potentially, could positively affect public health.