Jenny A. Visser

Anti-Müllerian hormone and folliculogenesis

This paper reviews the role of anti-Müllerian hormone, a member of the TGF(beta) family signaling through a BMP-like pathway, in the ovary. In vivo and in vitro studies showed that AMH has an inhibitory effect on primordial follicle recruitment and it decreases the sensitivity of follicles for the FSH-dependent selection for dominance. Besides its functional role in the ovary, AMH serum level serves as an excellent candidate marker of ovarian reserve.

Meta-analysis of genome-wide association data identifies two loci influencing age at menarche.

We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 × 10−9), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 × 10−9), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.

Anti-Müllerian hormone and its role in ovarian function.

Anti-Müllerian hormone (AMH) is expressed after birth in the ovary in the granulosa cells of healthy, small growing follicles. We have shown that AMH affects two important regulatory steps during folliculogenesis. At initial recruitment, AMH inhibits recruitment of primordial follicles into the growing pool, while at cyclic recruitment AMH lowers the FSH-sensitivity of follicles. In these ways, AMH plays an important role in regulation of ovarian follicle growth. AMH serum level is a strong candidate marker for ovarian reserve in women. In normo-ovulatory women, AMH serum levels correlated strongly with the number of antral follicles. In addition, AMH is a strong predictor for the number of oocytes retrieved in patients undergoing IVF treatment. The convenience of determination and its relative stable expression during the menstrual cycle indicate that further validation of the use of serum AMH is recommended as a clinical measure of ovarian reserve.

The activin A-follistatin system: potent regulator of human extracellular matrix mineralization

Bone quality is an important determinant of osteoporosis, and proper osteoblast differentiation plays an important role in the control and maintenance of bone quality. We investigated the impact of activin signaling on human osteoblast differentiation, extracellular matrix formation, and mineralization. Ac‐tivins belong to the transforming growth factor‐β su‐perfamily and activin A treatment strongly inhibited mineralization in osteoblast cultures, whereas the ac‐tivin antagonist follistatin increased mineralization. Os‐teoblasts produced activin A and follistatin in a differentiation‐dependent manner, leading to autocrine regulation of extracellular matrix formation and mineralization. In addition, mineralization in a vascular smooth muscle cell‐based model for pathological calcification was inhibited. Comparative activin A and fol‐listatin gene expression profiling showed that activin signaling changes the expression of a specific range of extracellular matrix proteins prior to the onset of mineralization, leading to a matrix composition with reduced or no mineralizing capacity. These findings demonstrate the regulation of osteoblast differentiation and matrix mineralization by the activin A‐follista‐tin system, providing the possibility to control bone quality as well as pathological calcifications such as atherosclerosis by using activin A, follistatin, or analogs thereof.—Eijken M., Swagemakers, S., Koedam, M., Steenbergen, C., Derkx, P., Uitterlinden, A. G., van der Spek P. J., Visser, J. A., de Jong F. H., Pols, H. A. P., van Leeuwen J. P. T. M. The activin A‐follistatin system: potent regulator of human extracellular matrix mineralization. FASEB J. 21, 2949–2960 (2007)

Anti-Müllerian hormone and ovarian dysfunction

Anti-Müllerian hormone (AMH) has important roles in postnatal ovarian function. Produced by ovarian granulosa cells, AMH is involved in initial follicle development. In fact, serum AMH level correlates with ovarian follicle number. In patients with polycystic ovary syndrome (PCOS), AMH levels are elevated, which indicates its potential relevance in PCOS diagnosis and management. AMH represents a useful clinical marker for the assessment of ovarian reserve in cases of subfertility caused by advanced age in women. A potential role for AMH in dominant follicle selection has also been suggested. Future challenges comprise the availability of a well-standardized assay and the development of AMH agonists and antagonists as possible tools to manipulate ovarian function for contraception or ovarian longevity.

Assessment of ovarian reserve in adult childhood cancer survivors using anti-Müllerian hormone

BACKGROUND The aim was to assess possible treatment-induced gonadal damage in a cohort of adult female childhood cancer survivors (CCS) using anti-Müllerian hormone (AMH), the most sensitive marker of ovarian reserve. METHODS A total cohort of 185 survivors was compared with 42 control subjects. The median follow-up time was 18.1 years (range 4.1-43.2 year). RESULTS Median AMH concentrations in the analysed cohort were not different from controls (median 1.7 versus 2.1 microg/l; P = 0.57). However, AMH levels were lower than the 10th percentile of normal values in 27% (49/182) of our survivors. In addition, 43% (79/182) had AMH levels lower than 1.4 microg/l, a previously established cut-off value which predicts ongoing pregnancy after assisted reproduction. There were no differences in AMH levels in subgroups classified according to disease. However, survivors treated with three or more procarbazine containing chemotherapy cycles had significantly lower AMH levels than controls (median 0.5 microg/l; P = 0.004). Also survivors treated with abdominal or total body irradiation had significantly lower AMH levels than controls (median < 0.1 microg/l; P < 0.001). CONCLUSIONS AMH can be used to identify subgroups of CCS at risk for decreased fertility or premature ovarian failure. In these survivors, options for fertility preservation should be considered prior to starting treatment since they may be at risk for poor chances of pregnancy after assisted reproductive treatment.

Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiency

Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a disorder of infertility characterized by amenorrhoea, low estrogen levels and increased gonadotropin levels in women aged <40 years. POI is the result of premature exhaustion of the follicle pool or can be attributed to follicular dysfunction, for example, owing to mutations in the follicle-stimulating hormone receptor or steroidogenic cell autoimmunity. Moreover, advances in cancer therapeutics over the past decades have led to increasing survival rates for both paediatric and adult malignancies. Given the gonadotoxic effect of many cancer treatments, more women develop POI. A marker that predicts whether women are at risk of POI would, therefore, aid in early diagnosis and fertility counselling. Anti-Müllerian hormone (AMH), a growth factor produced solely by small, growing follicles in the ovary, might constitute such a marker, as serum levels of this hormone correlate strongly with the number of growing follicles. In addition, AMH could potentially help assess the progression of ovarian senescence, as serum AMH levels are independent of hypothalamic–pituitary–gonadal axis function and decrease to undetectable levels at menopause. In cancer survivors, serum AMH levels correlate with the extent of gonadal damage. In this Review, we provide an overview of the current studies that have measured AMH in women with POI of various aetiologies and discuss its possible application as a marker to determine ovarian reserve.

Serum Anti-Mullerian Hormone Levels in Healthy Females: A Nomogram Ranging from Infancy to Adulthood

CONTEXT Anti-müllerian hormone (AMH) is an accurate marker of ovarian reserve. However, sufficiently large sets of normative data from infancy to the end of reproductive life are scarce. OBJECTIVE This study was an assessment of serum AMH levels in healthy females. SUBJECTS In 804 healthy females ranging from infancy until the end of the reproductive period, serum AMH levels were measured with an enzyme-linked immunometric assay. All adults had regular menstrual cycles. The majority was proven fertile and none of them had used oral contraceptive pills prior to study inclusion. RESULTS In the total cohort, AMH was inversely correlated with age (r = -0.24; P < 0.001). The age at which the maximum AMH value was attained was at 15.8 yr. In girls younger than 15.8 yr, serum AMH and age were positively correlated (r = +0.18; P = 0.007). Thereafter AMH levels remained stable (r = -0.33; P = 0.66), whereas from the age of 25.0 yr onward, an inverse correlation between AMH and age (r = -0.47; P < 0.001) was observed. At any given age, considerable interindividual differences in serum AMH levels were observed. CONCLUSION During infancy AMH levels increase, whereas during adolescence, a plateau until the age of 25 yr was observed. From the age of 25 yr onward, serum AMH levels correlate inversely with age, implying that AMH is applicable as a marker of ovarian reserve only in women of 25 yr old and older. Our nomogram may facilitate counseling women on their reproductive potential.

Loci at chromosomes 13, 19 and 20 influence age at natural menopause

We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; –0.4 year per T allele (39%); P = 6.3 × 10−11), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10−11) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10−8). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

Anti-Mullerian hormone: a marker for oocyte quantity, oocyte quality and embryo quality?

Serum anti-Müllerian hormone (AMH) concentrations decline with increasing age and constitute a sensitive marker for ovarian ageing. In addition, basal serum AMH concentrations predict ovarian response during IVF cycles. Concomitantly, oocyte quantity and embryo quality decrease with advancing age. Hence, it was postulated that AMH in serum constitutes a marker for embryo quality. Women aged 37 years and younger with regular menstrual cycles, normal body mass index and partners with normal semen parameters were randomly assigned to either a standard or mild stimulation protocol for IVF treatment. Blood samples were drawn at cycle day 3 and at the day of human chorionic gonadotrophin administration. Embryo quality was assessed using embryo morphology score and preimplantation genetic screening. Serum AMH concentrations on cycle day 3 were correlated with the number of oocytes retrieved in both groups. AMH and embryo morphology were correlated after mild stimulation, but not after conventional ovarian stimulation. AMH and the chromosomal competence of embryos were not correlated. Serum AMH is predictive for ovarian response to stimulation. However, the lack of a consistent correlation with embryo morphology and embryo aneuploidy rate is not in favour of a direct relationship between oocyte quantity and embryo quality.