Primary Amenorrhea and Premature Ovarian Insufficiency.

This review focuses on primary amenorrhea and primary/premature ovarian insufficiency due to hypergonadotropic hypogonadism. Following a thoughtful, thorough evaluation, a diagnosis can usually be discerned. Pubertal induction and ongoing estrogen replacement therapy are often necessary. Shared decision-making involving the patient, family, and health-care team can empower the young person and family to successfully thrive with these chronic conditions.

Ovarian Insufficiency and Fertility Preservation During and After Childhood Cancer Treatment.

Premature ovarian insufficiency (POI) is one of many potential long-term consequences of childhood cancer treatment in females. Causes of POI in this patient population can include chemotherapy, especially alkylating agents, and radiation therapy. Rarely, ovarian tumors lead to ovarian dysfunction. POI can manifest as delayed pubertal development, irregular menses or amenorrhea, and infertility. This diagnosis often negatively impacts emotional health due to the implications of impaired ovarian function after already enduring treatment for a primary malignancy. The emerging adult may be challenged by the impact on energy level, quality of life, and fertility potential. POI can also lead to low bone density and compromised skeletal strength. This review discusses the health consequences of POI in childhood cancer survivors (CCS). We also explore the role of fertility preservation for CCS, including ovarian tissue cryopreservation and other available options. Lastly, knowledge gaps are identified that will drive a future research agenda.

Impact of ovarian insufficiency on bone health in childhood cancer survivors: Two cases.

PURPOSE: To investigate the skeletal phenotype of adolescent girls with premature ovarian insufficiency (POI). METHODS: Data are presented from two adolescent girls who participated in a clinical research protocol to evaluate axial bone mineral density (BMD) (via dual-energy x-ray absorptiometry, DXA) and appendicular bone density, microarchitecture, and strength (via high-resolution peripheral quantitative computed tomography, HRpQCT). Anthropometric data were also obtained, and pubertal staging was performed by a clinician. RESULTS: Both cases presented with an undetectable estradiol concentration and an elevated follicle stimulating hormone (FSH), meeting the criteria for POI. Each also received alkylating agents as part of their chemotherapy and radiotherapy, but in different locations as one presented with stage IV neuroblastoma and the other, metastatic medulloblastoma. Both had a low BMD of the axial and appendicular skeleton, as well as microarchitectural changes of the latter. The low BMD Z-score (<-2.0) seen when interpreting their DXA measurements for chronological age improved when adjusted for short stature, but it was not normalized. Lastly, most variables obtained by HRpQCT were abnormal for each participant, indicating that appendicular bone structure and strength were compromised. CONCLUSIONS: Chemotherapy and radiation affect growth, puberty, and bone accrual deleteriously. However, as these cases show, POI in an adolescent is not always classic primary ovarian insufficiency. Adolescents with brain cancer can present with signs of estrogen deficiency but may not be able to secrete FSH to the extent of elevation typically seen in long-term cancer survivors. Estrogen deficiency is almost universally present in either clinical setting and prompt recognition facilitates early provision of hormone replacement therapy that may then allow for a resumption of bone accrual as an adolescent approaches her peak bone mass.

My 28 Days - a global digital women's health initiative for evaluation and management of secondary amenorrhea: case report and literature review.

There is a need to close the gap between knowledge and action in health care. Effective care requires a convenient and reliable distribution process. As global internet and mobile communication increase capacity, innovative approaches to digital health education platforms and care delivery are feasible. We report the case of a young African woman who developed acute secondary amenorrhea at age 18. Subsequently, she experienced a 10-year delay in the diagnosis of the underlying cause. A global digital medical hub focused on women's health and secondary amenorrhea could reduce the chance of such mismanagement. Such a hub would establish more efficient information integration and exchange processes to better serve patients, family caregivers, health care providers, and investigators. Here, we show proof of concept for a global digital medical hub for women's health. First, we describe the physiological control systems that govern the normal menstrual cycle, and review the pathophysiology and management of secondary amenorrhea. The symptom may lead to broad and profound health implications for the patient and extended family members. In specific situations, there may be significant morbidity related to estradiol deficiency: (1) reduced bone mineral density, 2) cardiovascular disease, and 3) cognitive decline. Using primary ovarian insufficiency (POI) as the paradigm condition, the Mary Elizabeth Conover Foundation has been able to address the specific global educational needs of these women. The Foundation did this by creating a professionally managed Facebook group specifically for these women. POI most commonly presents with secondary amenorrhea. Here we demonstrate the feasibility of conducting a natural history study on secondary amenorrhea with international reach to be coordinated by a global digital medical hub. Such an approach takes full advantage of internet and mobile device communication systems. We refer to this global digital women's health initiative as My 28 Days®.

Yoga as an intervention to promote bone and mental health in adolescent females with anorexia nervosa: a pilot study.

In this randomized pilot study, we examined the effects of yoga intervention on axial and peripheral bone mineral density (BMD), disordered eating cognitions, anxiety, and depression in adolescent girls with anorexia nervosa (AN). Fifteen young women aged 13-18 years with AN or atypical AN were randomized to either a Yoga group (n = 7), including twice-weekly yoga for 24 weeks plus standard outpatient care, or Non-Yoga group (n = 8), who received standard outpatient care alone. Data from anthropometrics, mental health and eating behavior questionnaires, dual-energy x-ray absorptiometry, and peripheral quantitative computed tomography measurements were obtained at baseline and 6 months. The adjunct of yoga to standard treatment resulted in statistically significant improvement of axial BMD, depression, and disordered eating cognitions in comparison to the Non-Yoga group. In conclusion, a gentle yoga intervention may be beneficial for improving bone and mental health in adolescent females with AN.

Associations of urinary metabolite concentrations of phthalates and phthalate replacements with body composition from mid-childhood to early adolescence.

BACKGROUND: Phthalates may adversely influence body composition by lowering anabolic hormones and activating peroxisome-proliferator activated receptor gamma. However, data are limited in adolescence when body mass distributions rapidly change and bone accrual peaks. Also, potential health effects of certain phthalate/replacements [e.g., di-2-ethylhexyl terephthalate (DEHTP)] have not been well studied. METHODS: Among 579 children in the Project Viva cohort, we used linear regression to evaluate associations of urinary concentrations of 19 phthalate/replacement metabolites from mid-childhood (median: 7.6 years; 2007-2010) with annualized change in areal bone mineral density (aBMD) and lean, total fat, and truncal fat mass as measured by dual-energy X-ray absorptiometry between mid-childhood and early adolescence (median: 12.8 years). We used quantile g-computation to assess associations of the overall chemical mixture with body composition. We adjusted for sociodemographics and tested for sex-specific associations. RESULTS: Urinary concentrations were highest for mono-2-ethyl-5-carboxypentyl phthalate [median (IQR): 46.7 (69.1) ng/mL]. We detected metabolites of most replacement phthalates in a relatively small number of participants [e.g., 28% for mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP; metabolite of DEHTP)]. Detectable (vs. non-detectable) MEHHTP was associated with less bone and greater fat accrual in males and greater bone and lean mass accrual in females [e.g., change in aBMD Z-score/year (95% CI): -0.049 (-0.085, -0.013) in males versus 0.042 (0.007, 0.076) in females; pinteraction<0.01]. Children with higher concentrations of mono-oxo-isononyl phthalate and mono-3-carboxypropyl phthalate (MCPP) had greater bone accrual. Males with higher concentrations of MCPP and mono-carboxynonyl phthalate had greater accrual of lean mass. Other phthalate/replacement biomarkers, and their mixtures, were not associated with longitudinal changes in body composition. CONCLUSIONS: Concentrations of select phthalate/replacement metabolites in mid-childhood were associated with changes in body composition through early adolescence. As use of phthalate replacements such as DEHTP may be increasing, further investigation can help better understand the potential effects of early-life exposures.

Trends in Pregnancy Rates in an Urban Adolescent Clinic Before and During the COVID-19 Pandemic.

We examined COVID-19 pandemic-related changes on reproductive health care delivery and pregnancy rates in an adolescent clinic. Through a retrospective data collection as part of quality improvement project, we compared the number of pregnancies, visit percentages for newly diagnosed pregnancies, and number/percentage of long acting reversible contraception (LARC) visits. The percentage of visits for newly diagnosed pregnancies during the first 3 months of the COVID-19 pandemic (April-June 2020) increased significantly relative to pre-pandemic percentages while the absolute number of new pregnancies only trended upward. Over the same timeframe, the total number of LARC visits decreased, although they consisted of a higher percentage of all in-person visits than pre-pandemic. After the first few months of the pandemic, these values returned to pre-pandemic levels. The substantial increase in the rate of new pregnancies during the first 3 to 6 months of the COVID-19 pandemic demonstrates the importance of prioritizing access to reproductive health care services for adolescents and young adults.

Characterizing the Adolescent Premature Ovarian Insufficiency Phenotype: A Case Control Study.

STUDY OBJECTIVES: To characterize the skeletal, cardiometabolic, cognitive, and mental health phenotype of adolescents with idiopathic premature ovarian insufficiency (POI) DESIGN: Case control SETTING: Pediatric tertiary referral center in Cincinnati, Ohio PARTICIPANTS: Nine adolescents (ages 11-18.99 years) with newly diagnosed POI and 9 normally menstruating controls, matched by age and body mass index MAIN OUTCOME MEASURES: Between-group comparisons of bone characteristics assessed by dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), psychosocial health (anxiety, depression, and quality of life), and cognition and memory by questionnaire RESULTS: Adolescents with POI had lower bone density Z-scores by DXA (lumbar spine -1.93 vs 0.80; whole body less head -2.05 vs 0.00; total hip -1.03 vs 0.83; and femoral neck -1.23 vs 0.91; all P < .001), as well as lower trabecular volumetric bone mineral density (tibia 3% site 226 vs 288 mg/mm3, P < .001; radius 3% site 200 vs 251, P = .001), smaller cortical area (tibia 66% site 251 vs 292 mm2, P = .028), and thickness (tibia 66% site 3.56 vs 4.30 mm, P = .001) than controls. No abnormalities in cardiometabolic biomarkers were detected in POI cases. Adolescents with POI were also more likely to report low energy (78% vs 22%, P = .02). CONCLUSION: Estrogen deficiency adversely affects bone health in adolescents with POI. However, we did not find associations with cardiometabolic, mental health, or cognitive outcomes in this small sample.

Relationship Between Hypovitaminosis D and Fractures Among Adolescents With Overweight or Obesity.

Adolescents with overweight/obesity are at risk for vitamin D insufficiency and deficiency. Both overweight/obesity and vitamin D insufficiency/deficiency may predispose to fractures. We enrolled 103 participants (53.3% females, 15.9 ± 2.2 years) in a retrospective case-control study to determine whether an association exists between fractures and a low 25-hydroxyvitamin D (25[OH]D) among adolescents whose body mass index (BMI) ≥ 85 percentile. Cases (n = 28) sustaining a low/medium impact fracture were matched to controls (n = 75) without a fracture history. A conditional-logistic regression analysis addressing the common vitamin D insufficiency/deficiency cutoffs was used. Overweight, obesity, and significant obesity rates were 10.7%, 53.4%, and 35.9%, respectively. Mean (±SD) 25(OH)D was 16.5 ± 6.4 ng/mL. In all, 25(OH)D insufficiency rates (level <20 ng/mL) were 70.5%. Matched cases and controls had similar 25(OH)D insufficiency/deficiency rates (P > .05). Controlling for race and seasonality showed no association between fractures and 25(OH)D insufficiency/deficiency (P > .05). These data suggest that fractures are not associated with low 25(OH)D levels among adolescents whose BMI ≥ 85th percentile.

Changes in Bone Marrow Adipose Tissue in Transgender and Gender Non-Conforming Youth Undergoing Pubertal Suppression: A Pilot Study.

Pubertal suppression with gonadotropin-releasing hormone (GnRH) agonists in transgender and gender non-conforming (TGNC) youth may affect acquisition of peak bone mass. Bone marrow adipose tissue (BMAT) has an inverse relationship with bone mineral density (BMD). To evaluate the effect of pubertal suppression on BMAT, in this pilot study we prospectively studied TGNC youth undergoing pubertal suppression and cisgender control participants with similar pubertal status over a 12-month period. BMD was measured by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Magnetic Resonance T1 relaxometry (T1-R) and spectroscopy (MRS) were performed to quantify BMAT at the distal femur. We compared the change in BMD, T1-R values, and MRS lipid indices between the two groups. Six TGNC (two assigned female and four assigned male at birth) and three female control participants (mean age 10.9 and 11.7 years, respectively) were enrolled. The mean lumbar spine BMD Z-score declined by 0.29 in the TGNC group, but increased by 0.48 in controls (between-group difference 0.77, 95% CI: 0.05, 1.45). Similar findings were observed with the change in trabecular volumetric BMD at the 3% tibia site (-4.1% in TGNC, +3.2% in controls, between-group difference 7.3%, 95% CI: 0.5%-14%). Distal femur T1 values declined (indicative of increased BMAT) by 7.9% in the TGNC group, but increased by 2.1% in controls (between-group difference 10%, 95% CI: -12.7%, 32.6%). Marrow lipid fraction by MRS increased by 8.4% in the TGNC group, but declined by 0.1% in controls (between-group difference 8.5%, 95% CI: -50.2%, 33.0%). In conclusion, we observed lower bone mass acquisition and greater increases in BMAT indices by MRI and MRS in TGNC youth after 12 months of GnRH agonists compared with control participants. Early changes in BMAT may underlie an alteration in bone mass acquisition with pubertal suppression, including alterations in mesenchymal stem cells within marrow.

Bone marrow adiposity in pediatric Crohn's disease.

Patients with Crohn's disease often have low bone mineral density and an increased risk of osteoporosis. Although decreased bone formation can be seen at diagnosis, the underlying pathophysiology of suboptimal bone accrual remains poorly understood. We sought to evaluate a novel mechanism affecting osteogenesis in patients with Crohn's disease. In this case series, we evaluated bone marrow composition at the distal femur and proximal tibia of the left knee measured via magnetic resonance (MR) spectroscopy and relaxometry in five adolescents with the diagnosis of Crohn's disease. The subjects were enrolled prospectively between 2011 and 2013 at Boston Children's Hospital. Additional clinical information, including DXA scans to evaluate bone mineral density and body composition, and Crohn's disease history, such as glucocorticoid use and disease duration, were assessed. Healthy adolescents have persistent hematopoietic marrow with only 40 to 50 % fat in the long bone metaphyses. The current participants with Crohn's disease had increased marrow adiposity, with a mean fat fraction of 67.8 %. There appeared to be a trend towards higher fat fraction with shorter disease duration, while participants with the longest disease duration had the lowest fat fraction. Participants also had decreased bone density, increased fat mass, and lower lean mass, as assessed by DXA and compared to pediatric reference data. Our MRI results demonstrate increased marrow adiposity in children with Crohn's disease, especially early in the course of the disease. DXA may better demonstrate longer-term effects on bone. Additional studies are needed to evaluate bone marrow composition in these patients and to elucidate further the inverse relationship between marrow adipocytes and osteogenesis, as well as the relationship between bone marrow adiposity and body composition.

Bone density and bone marrow composition in transgender girls prior to pubertal blockade: A case series.

PURPOSE: To determine bone mineral density (BMD) of transgender girls before pubertal blockade, and correlate with lifestyle and clinical variables. METHODS: Six transfemale peri-pubertal girls had knee magnetic resonance imaging (MRI) with T1-weighted images and single-voxel proton magnetic resonance spectroscopy (MRS). BMD measurements were obtained via dual-energy X-ray absorptiometry. Questionnaires about physical activity, diet, and the Eating Attitudes Test (EAT-26) were completed. The T2 relaxation rate of water (R2 = 1/T2 in s -1) was correlated with scores on surveys. RESULTS: Three participants (50 %) had a low bone mineral density for age based on total body less head Z-score less than -2; two participants (33 %) had a low BMD for age at lumbar spine. All had EAT-26 scores below threshold for clinical concern. All participants self-reported regular exercise. Bone marrow MR variables (T1, fat fraction, unsaturation index and R2 of water) were not correlated with DXA measures. CONCLUSIONS: Participants had low BMD on beginning pubertal blockade. Clinicians should consider monitoring BMD among youth AMAB, a group at potential risk for poor bone health.

Serum PFAS and Urinary Phthalate Biomarker Concentrations and Bone Mineral Density in 12-19 Year Olds: 2011-2016 NHANES.

CONTEXT: Per- and polyfluoroalkyl substances (PFAS) and phthalates are 2 families of environmental endocrine disruptors that may be associated with areal lower bone mineral density (aBMD). OBJECTIVE: To examine associations between serum PFAS and urinary phthalate biomarker concentrations and their mixtures with aBMD Z-scores in adolescents. DESIGN, PATIENTS, AND MEASURES: We examined serial cross-sectional data from male (n = 453) and female (n = 395) 12- to 19-year-old participants in the 2011 through 2016 National Health and Nutrition Examination Survey with measures of serum PFAS, urinary phthalate metabolites, and dual-energy X-ray absorptiometry aBMD Z-scores (total body less head). In sex-specific models, we used linear regression to examine associations of individual PFAS and phthalate biomarkers with aBMD Z-scores, and Bayesian kernel machine regression to examine the association of the overall PFAS/phthalate biomarker mixture with aBMD Z-scores. We replicated the analysis, stratifying by race/ethnicity. RESULTS: Participants were (mean ±â€…SD) 15 ±â€…2.1 years of age. In males, each doubling of serum perfluorooctanoate (PFOA), perfluorooctane sulfonate, urinary mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate, and the overall PFAS/phthalate mixture was associated with a lower aBMD Z-score (eg, for PFOA: -0.24; 95% CI, -0.41 to -0.06). Serum PFOA and urinary MiBP were associated with higher aBMD Z-scores in females (eg, for PFOA: 0.09; 95% CI, -0.07 to 0.25). Findings did not differ by race/ethnicity. CONCLUSIONS: Certain PFAS and phthalates may be associated with reduced bone mineral density in adolescent males. Bone mineral density tracks across the life course, so if replicated in longitudinal cohorts, this finding may have implications for lifelong skeletal health.

Self-reported sleep characteristics and risk for incident vertebral and hip fracture in women.

OBJECTIVE: To examine the relationships between self-reported sleep characteristics and risk of incident vertebral fracture and hip fracture in women. DESIGN: Longitudinal cohort study. SETTING: Nurses' Health Studies (NHS: 2002-2014, NHSII: 2001-2015). PARTICIPANTS: Total 122,254 female registered nurses (46,129 NHS, 76,125 NHSII) without prior history of fracture. EXPOSURE: Sleep was characterized by 4 sleep-related domains-sleep duration, sleep difficulty, snoring, and excessive daytime sleepiness-assessed by self-reported questionnaires. OUTCOMES: Self-reports of vertebral fracture were confirmed by medical record review and hip fracture was assessed by biennial questionnaires. RESULTS: Over 12-14 years of follow-up, 569 incident vertebral fracture cases (408 in NHS, 161 in NHSII) and 1,881 hip fracture cases (1,490 in NHS, 391 in NHSII) were documented. In the pooled analysis, the multivariable-adjusted HR (95% CI) for vertebral fracture was 1.20 (0.86, 1.66) for sleep duration ≤5 hours vs. 7 hours and 0.82 (0.60, 1.12) for ≥9 vs. 7 hours; 1.63 (0.93, 2.87) for sleep difficulties all-the-time vs. none/little-of-the-time (p-trend = 0.005); 1.47 (1.05, 2.05) for snoring every night/week vs. never/occasionally (p-trend = 0.03), and 2.20 (1.49, 3.25) for excessive daytime sleepiness daily vs. never (p-trend < 0.001). In contrast, associations were not observed with hip fracture risk. CONCLUSION: Poorer sleep characteristics were associated with risk of vertebral fracture. Our study highlights the importance of multiple dimensions of sleep in the development of vertebral fractures. Further research is warranted to understand the role of sleep in bone health that may differ by fracture site, as well as sleep interventions that may reduce the risk of fracture.