Izaäk Schipper

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.

Anti-müllerian hormone as a marker of ovarian function in women after chemotherapy and radiotherapy for haematological malignancies

BACKGROUND In female cancer survivors, the accelerated loss of primordial follicles as a result of gonadal damage may lead to premature ovarian failure (POF). However, the extent of the damage is unpredictable. Anti-Müllerian hormone (AMH) constitutes a sensitive marker of ovarian reserve. Serum AMH levels were measured to assess sub-clinical ovarian damage in patients treated with gonadotoxic therapy. METHODS In 25 patients with haematological malignancies, serum AMH concentrations were measured prior to and after cancer therapy and were compared with normo-ovulatory controls. RESULTS In all patients, AMH concentrations were lower than controls prior to treatment. Thirteen patients were treated with multi-drug chemotherapy. Although in most patients treated with chemotherapy menstrual cyclicity was restored, median serum AMH levels were lower than in controls. Twelve patients had stem cell transplantation (SCT) after total body irradiation. They all developed POF and their serum AMH concentrations were undetectable. CONCLUSIONS Female cancer survivors treated with SCT all developed POF. Hence, in these patients fertility preservation should be considered. In patients treated with chemotherapy, ovarian reserve seems to be compromised as well.

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.

Normal human follicle development : an evaluation of correlations with oestradiol, androstenedione and progesterone levels in individual follicles

OBJECTIVE The mechanism of dominant follicle selection remains obscure.We have investigated the association between follicle diameter and follicular steroid levels in individual human ovarian follicles throughout the menstrual cycle.

Levels of Serum Anti–Müllerian Hormone, a Marker for Ovarian Reserve, in Women With Rheumatoid Arthritis

Fertility is reduced in women with rheumatoid arthritis (RA), even before diagnosis. This may be due to a diminished ovarian reserve. The current study examined serum levels of anti–Müllerian hormone (AMH), the most reliable endocrine marker for ovarian reserve, in early RA patients and the influence of disease activity and methotrexate (MTX) use on AMH concentrations.

Pregnancy outcome in female childhood cancer survivors

BACKGROUND The number of childhood cancer survivors has dramatically increased and consequently, an increasing number of survivors may now wish to conceive. Recently, several studies have described that previous treatment with abdominal radiotherapy may increase the risk of adverse pregnancy outcome. METHODS We conducted a retrospective single centre cohort study of childhood cancer survivors with a singleton live birth between January 2000 and December 2005. Pregnancy outcome was compared with data from the Netherlands Perinatal Registry, a nationwide database of pregnancy outcome parameters of all births in the Netherlands registered by midwives, obstetricians and paediatricians. RESULTS Data were available on 40 survivors and 9031 controls. Median age at diagnosis was 6.9 years (range 0.1-16.8 years). The median interval between diagnosis and date of delivery was 21.6 years (range 7.4-36.1 years). In the whole cohort, pregnancy outcome was not different between survivors and controls. However, survivors treated with abdominal radiotherapy delivered preterm and had post-partum haemorrhage (mean gestational age in survivors = 34.9 versus 39.2 weeks in controls, P = 0.001; 33% in survivors versus 5% in controls, P = 0.007, respectively). The offspring of survivors had normal birthweight after adjustment for gestational age (mean birthweight in offspring of survivors 2503 versus 1985 g; P = 0.22). CONCLUSION Childhood cancer survivors irradiated to the abdomen have an earlier delivery and higher incidence of post-partum haemorrhage. This stresses the need for close monitoring of the delivery, including inpatient perinatal care, in this group of childhood cancer survivors.

Circulating immunoreactive and bioactive follicle stimulating hormone concentrations in anovulatory infertile women and during gonadotrophin induction of ovulation using a decremental dose regimen

Our purpose was to determine whether decreased follicle stimulating hormone (FSH) activity, either systemic or at the follicular level, is involved in impaired follicle growth associated with normogonadotrophic anovulation. To differentiate between the possible levels of disturbance, bioactive (BIO-FSH; using the in-vitro rat granulosa cell aromatase bioassay) and immunoreactive (IRMA-FSH) FSH serum concentrations of three groups of subjects were compared: (i) 172 normogonadotrophic anovulatory infertile women during baseline conditions, (ii) 22 clomiphene-resistant polycystic ovary syndrome patients undergoing ovulation induction by exogenous gonadotrophins using a decremental dose regimen, and (iii) nine regularly cycling controls. BIO-FSH [13.2 (range 0.8-29.5) IU/l] and IRMA-FSH [4.4 (range 1.2-9.3) IU/l] concentrations in anovulatory women during baseline conditions were significantly lower than maximum concentrations reached during the follicular phase in controls [18.7 (13.2-23.4) and 6.4 (5.7-10.0) IU/l respectively], but were not significantly different from initial concentrations in controls [10.4 (7.2-19.6) and 4.8 (2.8-8.2) IU/l respectively]. Moreover, concentrations of IRMA-FSH and BIO-FSH were negatively correlated (r = -0.25, P = 0.01, and r = -0.24, P = 0.02 respectively) with the interval between last vaginal bleeding and blood sampling. Maximum concentrations of IRMA-FSH [7.6 (3.9-10.9) IU/l] during ovulation induction by gonadotrophins were not significantly different from maximum [6.4 (5.7-10.0) IU/l] concentrations in controls, whereas maximum BIO-FSH concentrations [13.5 (8.7-17.4) versus 18.7 (13.2-23.4) IU/l] were significantly lower. Our findings suggest that (i) circulating FSH does not reach concentrations that are sufficient to induce normal follicle development in anovulatory women during baseline conditions, and (ii) the FSH threshold for ovarian stimulation of this patient group is not different from normal.

Serum anti-Müllerian hormone and inhibin B concentrations are not useful predictors of ovarian response during ovulation induction treatment with recombinant follicle-stimulating hormone in women with polycystic ovary syndrome

OBJECTIVE To describe changes of anti-Müllerian hormone (AMH) and inhibin B during low-dose gonadotropin ovulation induction (OI) treatment in women with polycystic ovary syndrome (PCOS), and thus disturbed selection of the dominant follicle. DESIGN Observational study. SETTING A referral fertility clinic. PATIENT(S) Women with PCOS (n = 48) and normo-ovulatory women (n = 23). INTERVENTION(S) AND MAIN OUTCOME MEASURE(S) Serum AMH, inhibin B, FSH, and E(2) concentrations were measured at start of stimulation, on the day of follicle selection, and at administration of hCG during OI cycles and were compared with concentration measured during the normal menstrual cycle. RESULT(S) Development of a single dominant follicle was observed in 92% of all OI cycles, reflected by similar E(2) concentrations compared with those in spontaneous cycles. AMH concentrations were constant during low-dose ovarian stimulation. Inhibin B concentrations remained elevated in patients with PCOS, suggesting prolonged survival of small antral follicles, whereas in controls inhibin B concentrations declined during the late follicular phase. CONCLUSION(S) The lack of change in AMH and inhibin B concentrations suggest that follicle dynamics during low-dose stimulation seem different from those during controlled ovarian hyperstimulation. In addition, constant AMH and inhibin B levels suggest that neither AMH nor inhibin B is an accurate marker of ovarian response after low-dose gonadotropin OI in patients with PCOS.