Low Energy Availability Interferes With Exercise-Associated Bone Effects in Female Long-Distance Triathletes as Detected by HR-pQCT.

Female Athlete Triad, initially described as the association of disordered eating, amenorrhea and osteoporosis, was further redefined to focus on low energy availability (EA), which has a central role in development of hypoestrogenism and low bone mineral density (BMD). However, the contribution of each variable, that is, low EA and hypoestrogenism, for bone derangements is still an open question. To evaluate body composition and bone status in long-distance triathletes without hypoestrogenism, as compared to non-athletes, using DXA and HR-pQCT, and the influence of EA. Population comprised 23 triathletes who had completed at least one long-distance race in the previous year, and 17 non-athletic healthy controls. The athletes denied previous oligo-amenorrhea and had spontaneous regular menses or were on hormonal contraceptives. Control patients also had regular menses. Energy deficiency (low EA) was defined as energy intake below the recommended level for athletes, that is, 45 kcal/kg free fat mass/day. Only femoral neck BMD Z-score measured by DXA trended higher in athletes (p = 0.05), whereas high-resolution peripheral quantitative computed tomography detected significantly higher values of entire bone and trabecular bone area, cortical perimeter, trabecular vBMD and trabecular bone volume/tissue volume, and lower trabecular separation and trabecular inhomogeneity in athletes. No difference was found between athletes with spontaneous menses and those on hormone contraceptives in respect to all parameters. The effects of exercise on bone were not so pronounced in athletes with low EA, although they still had better bone parameters than controls. Stress fractures were reported by 4:12 athletes with low EA and by 2:11 athletes with adequate EA. Long-distance female triathletes without hypoestrogenism show higher values of cortical perimeter, bone area, volumetric density and trabecular microstructure, but low EA interferes with exercise-associated bone effects. These innovative findings reinforce the importance of adequate EA in female athletes to guarantee skeletal health.

Features of polycystic ovary syndrome (PCOS) in women with functional hypothalamic amenorrhea (FHA) may be reversible with recovery of menstrual function.

OBJECTIVE: Since features of polycystic ovary syndrome (PCOS) have been found to be prevalent in women with functional hypothalamic amenorrhea (FHA), we wished to determine what happens to these features after recovery of menstrual function in FHA Design: Prospective cohort study. Twenty-eight women with FHA and 30 age-matched ovulatory controls were studied. METHODS: Twenty-eight women with FHA and 30 age-matched ovulatory controls were studied. We measured serum estradiol, LH, FSH, testosterone, DHEAS, anti-Mullerian hormone (AMH), body mass index, and ovarian morphology on transvaginal ultrasound. RESULTS: At baseline, 12 of the 28 women (43%) had increased AMH (>4.7 ng/mL), and higher testosterone and larger ovaries compared to the other 16 women with normal AMH. One year after recovery of menstrual function, in the 12 women with increased AMH, serum AMH, testosterone and ovarian size decreased, while LH and estradiol increased. At one year, only one of the 12 women in the high AMH group developed clinical features of PCOS. CONCLUSIONS: In the majority of women with FHA who have PCOS-like features, these features may be due to the hypothalamic state and appear to be reversible. Few women may develop clinical PCOS after recovery.

Impact of low-weight severity and menstrual status on bone in adolescent girls with anorexia nervosa.

Clinicians currently use different low-weight cut-offs both to diagnose anorexia nervosa (AN) and to determine AN severity in adolescent girls. The purpose of this study was to evaluate the clinical utility of existing cut-offs and severity criteria by determining which are most strongly associated with risk for low bone mineral density (BMD). Height adjusted BMD Z scores were calculated for 352 females: 262 with AN and 90 healthy controls (controls) (12-20.5 years), using data from the BMD in Childhood Study, for the lumbar spine, whole body less head, and total hip. For most cut-offs used to define low weight (5th or 10th BMI percentile, BMI of 17.5 or 18.5, and 85 or 90% of median BMI), AN had lower BMD Z scores than controls. AN at >85 or >90% expected body weight for height (EBW-Ht) did not differ in BMD Z scores from controls, but differed significantly from AN at ≤85 or ≤90% EBW-Ht. Among AN, any amenorrhea was associated with lower BMD. AN had lower BMD than controls across DSM-5 and The Society for Adolescent Health and Medicine (SAHM) severity categories. The SAHM moderate severity classification was differentiated from the mildly malnourished classification by lower BMD at hip and spine sites. Amenorrhea and %EBW-Ht ≤ 85 or ≤ 90% are markers of severity of bone loss within AN. Among severity categories, BMI Z scores (SAHM) may have the greatest utility in assessing the degree of malnutrition in adolescent girls that corresponds to lower BMD.

A case of severe proximal focal femoral deficiency with overlapping phenotypes of Al-Awadi-Raas-Rothschild syndrome and Fuhrmann syndrome.

Proximal focal femoral deficiency (PFFD) is a heterogeneous disorder characterized by various degrees of femoral deficiencies and associated anomalies of the pelvis and lower limbs. The etiology of the disease has not been determined. We report on a 3-year-old boy with severe PFFD, who showed almost completely absent femora and fibulae, malformed pelvis and ectrodactyly of the left foot. These features were partially overlapped with those of Al-Awadi-Raas-Rothschild syndrome or Fuhrmann syndrome, both of which are caused by WNT7A mutations. Molecular analysis of our case, however, demonstrated no disease-causing mutations in the WNT7A gene.

Embolization of angiographically visible type I and II utero-ovarian anastomoses during uterine artery embolization for fibroid tumors: impact on symptom recurrence and permanent amenorrhea.

PURPOSE: To compare the incidences of symptom recurrence and permanent amenorrhea following uterine artery embolization (UAE) for symptomatic fibroid tumors in patients with type I and II utero-ovarian anastomoses (UOAs) with versus without ovarian artery embolization (OAE). MATERIALS AND METHODS: A retrospective, institutional review board-approved study of 99 women who underwent UAE for symptomatic fibroid tumors from April 2005 to October 2010 was conducted to identify patients who had type I or II UOAs at the time of UAE. Based on the embolization technique, patients were categorized into standard (ie, UAE only), combined (ie, UAE and OAE), and control (patients without UOAs who underwent UAE) groups. Data collected included patient characteristics, procedural technique and findings, symptom recurrence, secondary interventions, and permanent amenorrhea. Statistical analysis was performed with the Fisher exact test, with significance reached at P < .05. RESULTS: Twenty patients (20.2%; mean age, 46.9 y ± 6.3) had type I (n = 3) or II (n = 17) UOAs. Thirteen (65%) underwent UAE only (standard group) and seven (35%) underwent UAE and OAE (combined group). There were no significant differences between groups in demographics or in the incidence of permanent amenorrhea after procedures (follow-up, 561 d ± 490). There was a significantly higher incidence of symptom recurrence in the standard group compared with the control group (P = .01), with no differences between combined and control groups (P = 1). CONCLUSIONS: There were no statistical differences in permanent amenorrhea rates in the groups studied, with significantly higher symptom recurrence rates observed when OAE was not performed in the setting of UOA.

Hypothalamic amenorrhea in a Camurati-Engelmann disease--a case report.

OBJECTIVE: A case report of a patient diagnosed with Camurati-Engelmann Disease (CED) in association with the functional hypothalamic amenorrhea disturbances. CED is a very rare genetically determined disorder classified as a type of bone dysplasia. DESIGN: Case report. SETTING: Department of Gynecological Endocrinology, 3rd grade Medical University Hospital. PATIENT: Twenty-one years old female patient with CED admitted to the hospital because of primary amenorrhea. Her history revealed skeletal deformities and hearing impairment. METHODS: Clinical examination, ultrasound, laboratory evaluations (including serum gonadotropins (FSH, LH) at basal state and after stimulation with gonadotropin-releasing hormone, serum basal estradiol) radiological studies (X-ray of the head, the lumbar spine and lower extremities; a computed tomography of the head), G-banding karyotype, polymerase chain reaction and DNA sequencing. Hormonal serum evaluations were made using an enzyme-linked immunosorbent assay. The exon 4 of the transforming growth factor beta 1 gene was amplified by a polymerase chain reaction and the product was directly sequenced. RESULTS: The hormonal analysis was characteristic for the hypogonadotropic hypogonadism. Radiological and molecular analyses confirmed CED diagnosis. CONCLUSIONS: The hypothalamic amenorrhea in a patient with CED may be explained as a consequence of fat hypotrophy and very low body mass index. Therefore, impairment within hypothalamic-pituitary axis in patients with CED should be treated with special attention.

Combined clinical and ultrasound criteria could accurately predict the Y chromosome in primary amenorrhea patient.

This study aimed to assess the combined clinical and ultrasound criteria as a diagnostic tool for screening the Y chromosome related to primary amenorrhea. This cross-sectional study involving 59 subjects was taken from medical records at the Reproductive Immunoendocrinology Polyclinic of Cipto Mangunkusumo General Hospital, Jakarta, Indonesia. The medical records of subjects were then cross-checked with karyotyping analysis results. Sensitivity, specificity, and predictive values were analyzed to assess the criteria. Two subjects were presented with a Y chromosome, and one without a Y chromosome was misclassified into another group. After analysis, we found that combined clinical and ultrasound criteria could predict the Y chromosome related to primary amenorrhea with 95.9% accuracy, with sensitivity and specificity of 80% and 97.96%, respectively. Combined clinical and ultrasound criteria (introduced as Kanadi Sumapraja Criteria) could be used as a diagnostic tool for screening a Y chromosome related to primary amenorrhea.

Altered resting-state hippocampal functional connectivity in breast cancer survivors with chemotherapy-induced amenorrhea.

INTRODUCTION: Amenorrhea induced decrease of hormones is associated with cognitive impairment. This study aimed to evaluate hippocampal functional connectivity patterns in chemotherapy-induced amenorrhea (CIA) breast cancer (BC) patients, to evaluate the relationship between the functional connectivity features and hormone levels. METHOD: Neuropsychological test, functional magnetic resonance imaging, and assessment of hormone levels were conducted in 21 premenopausal BC patients before chemotherapy (t0 ) and 1 week after completing chemotherapy (t1 ). Twenty matched healthy controls (HC) were also included and underwent the same assessments at similar time intervals. Mixed effect analysis and paired t-test were used to compare differences in brain functional connectivity. RESULTS: Voxel-based paired t-tests revealed increased functional connectivity of the right and left hippocampus with the left fusiform gyrus, inferior and middle temporal gyrus, inferior occipital gyrus, left lingual gyrus, and parahippocampal gyrus after chemotherapy (p < .001) in CIA patients. Repeated measures analysis revealed significant group-by-time interactions in the left hippocampus with the bilateral fusiform gyrus, right parahippocampal gyrus, left inferior temporal gyrus, and left inferior occipital gyrus (p < .001). Premenopausal BC patients had no significant differences in cognitive function compared with HC at baseline. However, the CIA patients had high levels of self-rating depression scale, self-rating anxiety scale, total cholesterol, and triglycerides. Further, the CIA patients showed significant differences in hormone and fasting plasma glucose levels and cognitive performances between t0 and t1 (p < .05). Functional connectivity changes between the left hippocampus and the left inferior occipital gyrus was negatively correlated with E2 and luteinizing hormone changes (p < .05). CONCLUSION: The CIA patients had cognitive dysfunction mainly in memory and visual mobility. Chemotherapy may affect hippocampal-posterior cortical circuit which mediates visual processing in CIA patients. Moreover, E2 may be involved in this process.

Skeletal status and body composition in young women with functional hypothalamic amenorrhea.

CONTEXT: Functional hypothalamic amenorrhea (FHA) related to hypoestrogenism and hormonal status may influence skeletal homeostasis and body composition. The study aimed to evaluate hormones concentrations, body composition and bone strength in FHA cases. PATIENTS AND METHODS: Total body scans using DXA method (DPX-L, GE Lunar) were performed in a group of 27 women aged 21.8 years ± 3.9 with FHA related to weight loss. References of healthy control subjects were used to calculate Z-scores (age and gender matched), SD-scores (height and gender matched), and SDs-scores (weight and gender matched). Whole skeleton bone mineral content (TBBMC, g) and density (TBBMD, g/cm(2)), lumbar spine (L2-L4) bone mineral density (SBMD; g/cm(2)), lean body mass (LBM, g) and fat mass (FM, g) were investigated. Relative bone strength index was calculated as the TBBMC/LBM ratio. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, and prolactin (PRL) concentrations were assayed to characterize hormonal profile of FHA cases. RESULTS: Hormonal evaluation in patients with FHA revealed significantly decreased serum concentrations of gonadotropins and estradiol. Serum LH concentrations were 1.47 ± 0.89 mIU/ml, FSH 4.44 ± 1.94 mIU/ml. Estradiol concentrations in serum were 27.08 ± 13.10 pg/ml. As evidenced by Z-scores, FHA cases had decreased SBMD, TBBMD and TBBMC Z-scores of -1.23 ± 0.90 (p < 0.0001), -0.72 ± 0.86 (p < 0.001), and -0.90 ± 1.40 (p < 0.01), respectively. Reduced FM, LBM and FM/LBM ratio Z-scores of -1.80 ± 2.28 (p < 0.001), -0.59 ± 1.49 (p < 0.05) and -0.74 ± 1.55 (p < 0.05), but not TBBMC/LBM Z-score of -0.54 ± 2.14 (ns) were noted in FHA cases compared with healthy control cases. TBBMC, TBBMD, TBBMC/LBM when BH- or BW-matched were normal as evidenced by SD-scores and SDs-scores. SBMD remained reduced when BH-matched (SD-score = -0.40 ± 0.86; p < 0.05) whereas FM and FM/LBM were lower than expected in healthy, both compared to BH- and BW-dependent references. The length of amenorrhea in months negatively correlated with SBMD Z-score (R = -0.39, p < 0.05), and SD-scores for SBMD (R = -0.48), TBBMD (R = -0.43), TBBMC (R = -0.46) (all p < 0.05) and positively with SDs-scores for FM (R = 0.44, p < 0.05). CONCLUSION: Patients with FHA were characterized by lower concentrations of serum FSH, LH and estradiol concentrations. Moreover, FHA cases had decreased FM and an imbalanced relationship between BW, FM, and LBM. Despite reduced BMD and BMC, bone strength was not significantly affected by FHA.

Transvaginal Doppler sonography for evaluation of irregular uterine bleeding with DMPA.

BACKGROUND: The main cause for discontinuation of depot medroxyprogesterone acetate (DMPA) use is irregular menstrual bleeding. The exact pathophysiological mechanisms of irregular bleeding have remained unclear. Transvaginal Doppler is a non-invasive method for studying changes in blood flow which may highlight the underlying pathology in those cases with irregular uterine bleeding. The aim of this study was to quantify the uterine and subendometrial microvasculature in DMPA users with irregular bleeding pattern in comparison to DMPA users with amenorrhea. STUDY DESIGN: This is a case control study. Forty users of DMPA were divided into two groups: one group included 20 users with irregular uterine bleeding and the second group included 20 amenorrheic users. Pulsatility index (PI) and resistance index (RI) of uterine and subendometrial blood vessels were determined. Power Doppler Energy was used to quantify the signal percentage of the subendometrial area. RESULTS: There is significant reduction of PI and RI in the uterine artery and subendometrial microvasculature in cases of irregular uterine bleeding. CONCLUSION: Irregular uterine bleeding with DMPA associated with increased perfusion of uterine and subendometrial blood vessels.

A systematic approach to imaging the pelvis in amenorrhea.

This is a pictorial review on the radiological approach to patients with amenorrhea using a level-based framework. The prevalence of amenorrhea is 3 to 4% with wide-ranging causes involving multiple clinical disciplines. Normal menstruation depends on complex coordinated hormonal functions of the hypothalamic-pituitary-ovarian axis exerting its effect on an intact uterine end-organ and outflow tract. A disruption of any of these factors may result in amenorrhea. Categorizing the causes of primary and secondary amenorrhea into uterine, ovarian/gonadal, and intracranial levels provides a logical framework for its evaluation. A systematic level-based approach by targeted ultrasound of the pelvic structures is suggested, with different aims in primary versus secondary amenorrhea. Pelvic sonographic findings of various conditions within the uterine and ovarian/gonadal levels are illustrated. Conditions due to an intracranial cause result in downstream effects on the uterus and ovaries and can often be suspected based on a combination of clinical assessment, ultrasound findings, and laboratory investigations. By correlating pelvic ultrasound findings with underlying pathology, the clinical radiologist is able to provide useful diagnostic information in the management of these patients.

A novel homozygous Arg222Trp missense mutation in WNT7A in two sisters with severe Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.

Al-Awadi/Raas-Rothschild/Schinzel phocomelia (AARRS) syndrome, a rare autosomal recessive disorder, comprises malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. Mutations in WNT7A have been reported as cause of the syndrome. We report on two sisters in a Thai family with short and malformed long bones, absent fibulae, flexion contracture of digits, and a/hypoplastic nails. Fusion between severely malformed femora and slender tibiae has never been reported in patients with WNT7A mutations. Lower limbs were more severely malformed than the upper ones and the pelvis was also severely affected. Multiple fusions of long bones and of the femoral heads to the acetabula were evident. A novel homozygous missense mutation in coding exon 4 of the WNT7A was detected in both affected daughters (c.664C > T) leading to an amino acid exchange from arginine to tryptophan (p.Arg222Trp; R222W). The phenotype is likely to result from an abnormality of all three signaling centers in the developing limb resulting in ventralization with a loss of dorsal structures (aplasia/hypoplasia of nails) a loss of anterior-posterior identity (single distal bones in lower limb without polarity) and an outgrowth defect resulting in distal truncations.

Development of morphologically dominant follicles is associated with fewer metabolic disturbances in amenorrheic women with polycystic ovary syndrome: a pilot study.

OBJECTIVES: To determine if amenorrheic women with polycystic ovary syndrome (PCOS) demonstrate ultrasonographically detectable changes in follicle population. METHODS: Sixteen women with PCOS reporting the absence of menses for more than 3 months were enrolled in the study. Subjects had a physical examination, fasting blood tests and two transvaginal ultrasound scans spaced 1 month apart. In cases where evidence of a morphologically dominant follicle (≥ 10 mm in diameter) occurred, subsequent ultrasound scans were performed to determine the fate of the dominant follicle. Differences in total follicle population, maximum follicle diameter and clinical, hormonal and metabolic features were determined. RESULTS: Forty-four percent of subjects showed changes in follicle population of 6-10 follicles and 37% showed changes in follicle population of > 10. Maximum follicle diameters ranged between 5.4 and 33.0 mm. Four subjects demonstrated follicle diameters ≥ 10 mm. Of those who developed dominant follicles, two subjects ovulated, one subject developed a persistent anovulatory follicle and the dominant follicle regressed in the remaining subject. Diagnostic criteria for PCOS were similar among women that did or did not develop dominant follicles (menstrual cycle length, P = 0.880; hirsutism score, P = 0.809; free androgen index, P = 0.991; total follicle count, P = 0.199). However, lower glycosylated hemoglobin (P = 0.047) and insulin levels (P = 0.049) and better insulin sensitivity (P = 0.048) were noted in women who attained dominant follicles. CONCLUSION: Amenorrheic women with PCOS demonstrate changes in follicle population that are consistent with active follicle growth and regression despite prolonged periods of anovulation. Morphologic selection occurs in amenorrheic women and attainment of dominant follicles is associated with improved metabolic status.

Clinical, Hormonal, and Neuroradiological Characteristics and Therapeutic Outcomes of Prolactinomas in Children and Adolescents at a Single Center.

Background/Purpose: A prolactinoma is the most common pituitary adenoma, but it is relatively rare in childhood and adolescence. There is only limited research about the clinical spectrum, treatment, and outcomes of prolactinomas in childhood and adolescence. In this single-center cohort study, we assessed the clinical, hormonal, and neuroradiological characteristics and therapeutic outcomes of children and adolescents with prolactinomas. Methods: This retrospective cohort study included 25 patients with prolactinomas diagnosed before 19 years of age, who presented at Samsung Medical Center during a 15-year period (March 2005 to August 2019). Results: The median age at diagnosis was 16.9 (range 10.1-18.5) years, and 80% of the patients were female. The common clinical manifestations at diagnosis were galactorrhea (10/20, 50%) and amenorrhea (9/20, 45%) among females and visual field defects (3/5, 60%) and headaches (2/5, 40%) among males. In our cohort, macroadenomas accounted for 56% of cases, and the rate of overall responsiveness to dopamine agonists (DAs) was 56% (10/18). Male gender, the prolactin (PRL) level at diagnosis, and the presence of panhypopituitarism were positively correlated with maximum tumor diameter (r = 0.443, P = 0.026; r = 0.710, P < 0.001; and r = 0.623, P = 0.001, respectively). After the trans-sphenoidal approach (TSA), 53% (8/15) of patients showed normalization of the PRL level. Three patients, who underwent gamma knife surgery (GKS) owing to either resistance or intolerance to DAs or recurrence after the TSA, achieved a normal PRL level accompanied with marked tumor reduction and symptom remission. Conclusions: A macroprolactinoma is more prevalent than a microprolactinoma in children and adolescents than in adults. Male gender, increased PRL levels, and the presence of panhypopituitarism at diagnosis are closely related to macroprolactinomas in children and adolescents.

Ultrasound of the pediatric female pelvis.

Pelvic pain is a common indication for ultrasound examinations in female pediatric patients. Many pathological processes affect the female pelvis in childhood. Knowledge of the normal ultrasound appearance of the pelvic organs is the basis for the recognition of pathologic findings. Pelvic pain in children is a nonspecific clinical finding often prompting use of ultrasound. Other indications for pelvic ultrasound in female children include workup of cysts seen on fetal ultrasound, urogenital malformations in newborns, precocious puberty, vaginal discharge or abnormal bleeding, and amenorrhea. Knowledge of differential diagnosis for disease processes of the female pelvic organs is essential. Ultrasound is the imaging modality of choice for evaluating the pediatric female pelvis.

Ultrasound findings in amenorrhoeic women with vaginal bleeding.

OBJECTIVE OF STUDY: To document sonographically identifiable causes of vaginal bleeding in secondarily amenorrhoeic women of child bearing age. METHODS: A retrospective study of ultrasonographic findings among 102 secondarily amenorrhoeic women of childbearing age with vaginal bleeding was carried out. Ultrasound scan was carried using Siemens Sonoline SL1 equipment with 3.5MHz and 5.0MHz transducers RESULTS: 75(73.2%) patients had pregnancy-related conditions, 14(13.7%) had normal, non-pregnant uteri while the remaining 13 (12.8%) had other gynaecological conditions namely pelvic inflammatory disease (PID), uterine fibroids and ovarian masses. Though pregnancy-related conditions are the major causes of vaginal bleeding in amenorrhoeic women of childbearing age, PID, fibroids and ovarian masses are possible findings. CONCLUSION: Ultrasound examination is vital in the elucidation of vaginal bleeding in amenorrhoeic women. Pregnancy related conditions are not the only significant cause of amenorrhoea complicated by vaginal bleeding.

Bone Parameters in Anorexia Nervosa and Athletic Amenorrhea: Comparison of Two Hypothalamic Amenorrhea States.

Objective: We have reported low bone mineral density (BMD), impaired bone structure, and increased fracture risk in participants with anorexia nervosa (AN) and normal-weight oligoamenorrheic athletes (OAs). However, data directly comparing compartment-specific bone parameters in participants with AN, OAs, and controls are lacking. Design: A total of 468 female participants 14 to 21.9 years old were included: 269 with AN, 104 OAs, and 95 normal-weight eumenorrheic controls. Dual-energy x-ray absorptiometry was used to assess areal BMD (aBMD) of the whole body less head (WBLH), spine, and hip. High-resolution peripheral quantitative computed tomography was used to assess volumetric BMD (vBMD), bone geometry, and structure at the non-weight-bearing distal radius and weight-bearing distal tibia. Results: Participants with AN had lower WBLH and hip aBMD z scores than OAs and controls (P < 0.0001). Participants with AN and OAs had lower spine aBMD z scores than controls (P < 0.01). At the radius, total and cortical vBMD, percentage cortical area, and thickness were lower in the AN and OA groups than in controls (P ≤ 0.04); trabecular vBMD was lower in participants with AN than controls. At the tibia, participants with AN had lower measures for most parameters compared with OAs and controls (P < 0.05); OAs had lower cortical vBMD than controls (P = 0.002). Participants with AN and OAs had higher fracture rates than controls. Stress fracture prevalence was highest in OAs (P < 0.0001); nonstress fracture prevalence was highest in participants with AN (P < 0.05). Conclusion: AN is deleterious to bone at all sites and both bone compartments. A high stress fracture rate in OAs, who have comparable WBLH and hip aBMD measures to controls, indicates that BMD in these women may need to be even higher to avoid fractures.

A novel phenotype related to partial loss of function mutations of the follicle stimulating hormone receptor.

A single natural loss of function mutation of the follicle stimulating hormone receptor (FSHR) has been described to date. Present in the Finnish population it markedly impairs receptor function, blocking follicle development at the primary stage and presenting as primary amenorrhea with atrophic ovaries. When Western European women with this phenotype were examined for FSHR mutations the result was negative, suggesting that other etiologies corresponding to this clinical pattern are markedly more frequent. We now describe a novel phenotype related to mutations provoking a partial loss of function of the FSHR. A woman with secondary amenorrhea had very high plasma gonadotropin concentrations (especially FSH), contrasting with normal sized ovaries and antral follicles up to 5 mm at ultrasonography. Histological and immunohistochemical examination of the ovaries showed normal follicular development up to the small antral stage and a disruption at further stages. The patient was found to carry compound heterozygotic mutations of the FSHR gene: Ile160Thr and Arg573Cys substitutions located, respectively, in the extracellular domain and in the third intracellular loop of the receptor. The mutated receptors, when expressed in COS-7 cells, showed partial functional impairment, consistent with the clinical and histological observations: the first mutation impaired cell surface expression and the second altered signal transduction of the receptor. This observation suggests that a limited FSH effect is sufficient to promote follicular growth up to the small antral stage. Further development necessitates strong FSH stimulation. The contrast between very high FSH levels and normal sized ovaries with antral follicles may thus be characteristic of such patients.