Kirsten Holm

Serum Levels of Anti-Müllerian Hormone as a Marker of Ovarian Function in 926 Healthy Females from Birth to Adulthood and in 172 Turner Syndrome Patients

CONTEXT In adult women, anti-Müllerian hormone (AMH) is related to the ovarian follicle pool. Little is known about AMH in girls. OBJECTIVE The objective of the study was to provide a reference range for AMH in girls and adolescents and to evaluate AMH as a marker of ovarian function. SETTING The study was conducted at a tertiary referral center for pediatric endocrinology. MAIN OUTCOME MEASURES We measured AMH in 926 healthy females (longitudinal values during infancy) as well as in 172 Turner syndrome (TS) patients according to age, karyotype (A: 45,X; B: miscellaneous karyotypes; C: 45,X/46,XX), and ovarian function (1: absent puberty; 2: cessation of ovarian function; 3: ongoing ovarian function). RESULTS AMH was undetectable in 54% (38 of 71) of cord blood samples (<2; <2-15 pmol/liter) (median; 2.5th to 97.5th percentile) and increased in all (37 of 37) infants from birth to 3 months (15; 4.5-29.5 pmol/liter). From 8 to 25 yr, AMH levels were stable (19.9; 4.7-60.1 pmol/liter), with the lower level of the reference range clearly above the detection limit. AMH levels were associated with TS-karyotype groups (median A vs. B: <2 vs. 3 pmol/liter, P = 0.044; B vs. C: 3 vs. 16 pmol/liter, P < 0.001) as well as with ovarian function (absent puberty vs. cessation of ovarian function: <2 vs. 6 pmol/liter, P = 0.004; cessation of ovarian function vs. ongoing ovarian function: 6 vs. 14 pmol/liter, P = 0.001). As a screening test of premature ovarian failure in TS, the sensitivity and specificity of AMH less than 8 pmol/liter was 96 and 86%, respectively. CONCLUSION AMH seems to be a promising marker of ovarian function in healthy girls and TS patients.

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood

Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0–10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1–17.6) at bone marrow transplantation and 21.5 years (11.6–25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to −2.6 standard deviation scores (SDS) (−6.3 to −0.6), P = 0.002, and −2.6 SDS (−4.8 to −0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.

Bone Mass After Treatment for Acute Lymphoblastic Leukemia in Childhood

PURPOSETo study bone mass after childhood acute lymphoblastic leukemia (ALL) and determine if reduced bone mass is related to previous therapy or endocrine status at follow-up.PATIENTS AND METHODSWe studied 95 survivors of childhood ALL who were in first remission a median of 11 years (range, 3 to 23 years) after diagnosis and who had never been irradiated outside a cranial field. The bone mass was measured by dual-energy x-ray absorptiometry. The results were compared with data on 396 local controls.RESULTSAdjusted for sex and age, the mean whole-body bone mineral content (BMC) and bone mineral areal density (BMDA) were both significantly reduced (0.4 SDs less than the predicted mean value). This was mainly caused by reduced bone mass in the 33 participants who were aged 19 years or older at follow-up. In these young adults, the mean height for age, bone area for height, and BMC for bone area were all significantly reduced. This indicated that the reduced whole-body bone mass was caused by both reduced b...

Thyroid function in survivors of childhood acute lymphoblastic leukaemia : the significance of prophylactic cranial irradiation

OBJECTIVE Focus on long‐term side‐effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic‐pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversal.

Risk factors for reduced pulmonary function after malignant lymphoma in childhood

The aim was to study pulmonary function after Hodgkin disease or non-Hodgkin Lymphoma in childhood and to evaluate if younger age at diagnosis and therapy is a risk factor for reduced pulmonary function. We studied a population-based sample of survivors of Hodgkin disease (n = 22) or non-Hodgkin lymphoma (n = 19) in childhood. Pulmonary function test results were compared with reference values for our laboratory, generated by adjusting published reference values fit 348 healthy never-smokers from a local population study. Data were analyses as standardised residuals, which are [observed minus predicted value] divided by the residual standard deviation of the reference equations. At a median of 11 years after diagnosis (range 2 to 24), the participants had significantly reduced lung volumes and transfer factor, unrelated to the few pulmonary symptoms. On average, the total lung capacity was reduced to -0.9 standardised residual and the transfer factor was reduced to -1.3 standardised residual. Young age at therapy seemed to be a risk factor for reduced lung function, especially when treatment included thoracic irradiation. No significant toxic synergism was observed between smoking and previous cancer therapy. Therapy without thoracic irradiation but with doxorubicin and cyclophosphamide was almost as toxic to lung function as therapy with thoracic irradiation but without doxorubicin and cyclophosphamide. In conclusion, lung volumes and transfer factor were reduced several years after childhood Hodgkin disease of non-Hodgkin lymphoma, with young age at therapy as a risk factor, especially when combined with thoracic irradiation.

Bone mass and body composition after cessation of therapy for childhood cancer

Our aim was to review current information on body composition and bone mass after cessation of therapy for childhood cancer and to present preliminary data on body composition and bone mass in a group of Danish survivors of childhood leukaemia or lymphoma. Elevated body‐mass index (weight/height2; BMI) is frequent after treatment for childhood acute lymphoblastic leukaemia. BMI increases during therapy or within the first year after therapy and remains abnormal thereafter. Treatment with corticosteroids, abnormal growth‐hormone secretion after treatment with cranial irradiation (CI) or corticosteroids, younger age at diagnosis, or female gender were risk factors for elevated BMI in earlier studies. We evaluated 185 survivors of childhood leukaemia or lymphoma by dual‐energy X‐ray absorptiometry scanning. We found elevated whole‐body relative fat mass, which was associated with CI. Other studies found reduced bone mass in the radius, the lumbar spine and the whole body after treatment for childhood cancer. Growth‐hormone deficiency that is not adequately corrected, CI, reduced height or reduced weight were risk factors for reduced bone mass. In our 185 participants, the whole‐body bone mass was also reduced significantly compared with reference values. CI and older age at follow‐up were risk factors for reduced bone mass. We conclude that the elevated relative fat mass and reduced bone mass seen after treatment for childhood leukaemia or lymphoma is associated mainly with CI. Int. J. Cancer Supplement 11: 40–43, 1998.

Degree of fatness after allogeneic BMT for childhood leukaemia or lymphoma.

Excess fatness is frequent after childhood ALL treated without BMT. We measured the whole-body percent fat by dual-energy X-ray absorptiometry and the body-mass index (weight/height2 (kg/m2), BMI) in 25 survivors of childhood leukaemia or lymphoma (21 with ALL) who had received TBI and allogeneic BMT a median of 8 years ago (range 4–13). Adjusted for sex and age, the mean BMI was slightly but significantly reduced (0.4 s.d. below predicted) and the whole-body percent fat was significantly increased compared with healthy controls (1.1 s.d. above predicted). Eleven of 25 patients had a percent fat above the 90 percentile of the reference values, which indicates excess fatness. Adjusted for sex and age, a higher percent fat was related to additional cranial irradiation. Controlled for this, the whole-body percent fat seemed to be unrelated to age at BMT, length of follow-up, and previous chemotherapy. Compared with untransplanted ALL survivors treated with cranial irradiation, BMT survivors had significantly reduced BMI but similar whole body percent fat. BMI was a poor measure of body fatness in these patients. In conclusion, survivors of BMT for childhood leukaemia or lymphoma are adipose and slightly underweight and consequently have a substantially reduced lean body mass. Bone Marrow Transplantation (2001) 27, 817–820.

Uterus and ovaries in girls and young women with Turner syndrome evaluated by ultrasound and magnetic resonance imaging

Objective  To determine uterine and ovarian size in Turner syndrome (TS) and to compare uterine and ovarian size evaluated by transabdominal ultrasound (US) and magnetic resonance imaging (MRI) in girls with TS and two groups of controls.

Dosage of estradiol, bone and body composition in Turner syndrome - a 5 year randomized controlled clinical trial

OBJECTIVE Reduced bone mineral density (BMD) is seen in Turner syndrome (TS) with an increased risk of fractures, and body composition is characterized by increased body fat and decreased lean body mass. To evaluate the effect of two different doses of oral 17B-estradiol in young TS women on bone mineral density (BMD), biochemical markers of bone turnover and body composition with the hypothesis of a positive effect of the higher dose. DESIGN A double-blind 5-year randomized controlled clinical trial. 20 young TS women participated. Inclusion criteria were diagnosis of TS, age 15-25 years and current treatment with 2 mg oral estradiol daily. METHODS The low-dose (LD) group was administered 2 mg 17B-estradiol/day orally and placebo, the high-dose (HD) group was administered 2 + 2 mg 17B-estradiol/day orally. Main outcome measures were whole body and regional bone mineral density (BMD), lean body mass (LBM), fat mass (FM) measured yearly by DXA scan and resorptive and formative bone markers in serum. RESULTS BMD, whole body and regional, increased over time with an attenuation toward the end of the study, and bone turnover markers decreased over time, both with no differences between the treatment groups (P = 0.2-0.9). LBM increased significantly more in the HD group (P = 0.02). FM remained stable in both groups. CONCLUSIONS A steady increase in BMD over time in TS was found similar to healthy young women. The higher estrogen dose did not differentially affect BMD or bone markers. The positive effect on body composition may have long-ranging health benefits in TS.

Serum thyroglobulin as a marker of thyroid neoplasms after childhood cancer

Aim: To evaluate serum thyroglobulin (Tg) level as a marker of the development of thyroid disease when following individuals who Received neck irradiation therapy in childhood. Methods: In a non‐randomized cross‐sectional study Tg was assessed in 172 survivors of childhood cancer 10.8 y (1.9‐24) median (range) after diagnosis and 7.9 y. (0.9‐24.3) median (range) after the end of treatment. The patients were divided into two groups: group 1 included 47 patients who had Received irradiation to the neck and group 2 included 125 patients who did not receive irradiation to the neck. Results: Patients who had Received irradiation to the neck had significantly higher Tg levels compared with those who did not receive neck irradiation: median 14.0 (1.0–189.0) μg/L vs median 8.8, (0.7–112.2) μg/L (p < 0.001). Six out of seven patients with elevated Tg levels (>70 μg/L) had Received neck irradiation. Among these six patients, two patients developed secondary differentiated thyroid cancer and two patients developed benign thyroid neoplasms. None of the patients who had normal levels of Tg developed thyroid cancer.