Vien H. Vanderhoof

Bone Mineral Density in Estrogen-Deficient Young Women

CONTEXT Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. OBJECTIVE The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. DESIGN AND SETTING We conducted a cross-sectional study at a tertiary care research center. PARTICIPANTS We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353). PRIMARY OUTCOME MEASURE We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. RESULTS Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score <-2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (<32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below -2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. CONCLUSIONS Women with POI have lower bone density compared to regularly menstruating women. Compared to Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.

Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure.

OBJECTIVE To investigate the experiences of young women with spontaneous premature ovarian failure with regard to the initial presenting symptom, promptness of diagnosis, and patient education. METHODS We asked 50 patients previously diagnosed with spontaneous premature ovarian failure to participate in a structured interview survey consisting of 38 true‐or‐false, multiple‐choice, and open‐ended questions. RESULTS Disturbance in menstrual pattern was the most common initial symptom in the 48 women who completed the interview (44 of 48, 92%). Over half of the 44 women who presented with this complaint reported visiting a clinicians office three or more times before laboratory testing was performed to determine the diagnosis. Over half of them reported seeing three or more different clinicians before diagnosis. In 25% of women it took longer than 5 years for the diagnosis of premature ovarian failure to be established. Patients who spent more than 5 minutes with the clinician discussing the diagnosis were significantly more likely to be satisfied with the manner in which they were informed (P < .001). Ninety percent of participants were college graduates, and 40% had graduate degrees. CONCLUSION Women with spontaneous premature ovarian failure perceived a need for more aggressive evaluation of secondary amenorrhea and oligomenorrhea. Loss of menstrual regularity can be a sign of ovarian insufficiency, and the associated estrogen deficiency is a well‐established risk factor for osteoporosis.

Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure

BackgroundPremature Ovarian Failure (POF), defined as the development of hypergonadotropic amenorrhea before the age of 40 years, occurs in about 1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. Recently, in seven patients who presented with POF and white matter abnormalities on MRI (ovarioleukodystrophy) eight mutationswere found in EIF2B2, 4 and 5.MethodsTo further test the involvement of known mutations of EIF2B genes in POF, we screened 93 patients with POF who did not have identified leukodystrophy or neurological symptoms. We evaluated these eight mutations and two additional mutations that had been found in patients with milder forms of eIF2B-related disorders. We used restriction enzymes and direct sequencing.ResultsNone of the known mutations in EIF2B genes, either homozygous or heterozygous, were identified in our 93 patients with pure 46,XX POF. The upper 95 % confidence limit of the proportion 0/93 is 3.2%.ConclusionsWe conclude that eIF2B mutations, already described in cases of POF associated with white matter abnormalities, are an uncommon cause of pure spontaneous premature ovarian failure.

The psychosocial transition associated with spontaneous 46,XX primary ovarian insufficiency: illness uncertainty, stigma, goal flexibility, and purpose in life as factors in emotional health

OBJECTIVE To examine factors associated with emotional well-being in women with spontaneous primary ovarian insufficiency. DESIGN Cross-sectional and case-control study. SETTING Clinical research center, national U.S. health research facility. PATIENT(S) Women diagnosed with spontaneous 46,XX primary ovarian insufficiency (n = 100) at a mean age of 32.4 years and healthy control women of similar age (n = 60). INTERVENTION(S) Administration of validated self-reporting instruments. MAIN OUTCOME MEASURE(S) Illness uncertainty, stigma, goal disengagement/re-engagement, purpose in life, Positive and Negative Affect Schedule, Center of Epidemiologic Studies Depression Scale, State-Trait Anxiety Inventory. RESULT(S) Compared with controls, women with spontaneous primary ovarian insufficiency scored adversely on all measures of affect. Illness uncertainty and purpose in life were significant independent factors associated with anxiety (R(2) = 0.47), stigma and purpose in life were the significant independent factors associated with depression (R(2) = 0.51), and goal re-engagement and purpose in life were significantly and independently associated with positive affect (R(2) = 0.43). CONCLUSION(S) This evidence supports the need for prospective studies. Our findings are consistent with the hypothesis that clinicians could improve the emotional well-being of their patients with primary ovarian insufficiency by [1] informing them better about their condition, [2] helping them to feel less stigmatized by the disorder, and [3] assisting them in developing alternative goals with regard to family planning as well as other goals.

Depression in Women with Spontaneous 46, XX Primary Ovarian Insufficiency

CONTEXT A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI. OBJECTIVES We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI. DESIGN AND SETTING We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center. PATIENTS A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. MAIN OUTCOME MEASURES The structured clinical interview for DSM-IV was performed. RESULTS Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. CONCLUSIONS POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.

Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement.

CONTEXT Women with primary ovarian insufficiency have significantly lower serum estradiol and T levels compared with regularly menstruating women. They also have significantly reduced bone mineral density (BMD). OBJECTIVE The objective of the study was to evaluate the efficacy of hormone replacement in maintaining BMD in these young women. DESIGN AND SETTING This was a randomized, double-blind, single-center, placebo-controlled clinical trial at the National Institutes of Health clinical center (Bethesda, Maryland). PARTICIPANTS Young women with primary ovarian insufficiency participated in the study. INTERVENTIONS We compared the effect of estradiol and progestin replacement (n = 72) vs estradiol, progestin, and T replacement (n = 73) on BMD. We also compared findings with a contemporaneous control group of normal women (n = 70). All patients received transdermal estradiol (100 μg/d) plus oral medroxyprogesterone acetate 10 mg/d (12 d/mo) for a 3-month run-in period before being randomized in a double-blinded fashion to the addition of transdermal T (150 μg/d) or placebo. MAIN OUTCOME MEASURE Change in BMD at the femoral neck was measured by dual-energy x-ray absorptiometry. RESULTS At screening, patients had significantly lower femoral neck BMD compared with control women (0.77 vs 0.81 g/cm(2), P = .001) and did not differ in body mass index, age at menarche, or education level. Normal control women lost femoral neck BMD over the study period, whereas patients on estradiol and progestin therapy gained BMD; and at the end of the study period, femoral neck BMD of patients on estradiol and progestin therapy did not differ from that of control women (0.80 g/cm(2) in both groups, P = .9). The addition of T showed no further benefit (percentage change in BMD 3.9 vs 2.4, respectively, P = .9). Nonetheless, using a repeated-measures model, the T group achieved a mean BMD in the femoral neck 0.015 g/cm(2) higher than the placebo group at 3 years (95% confidence interval -0.005 to 0.034, P = .13). Similar findings were observed in the lumbar spine BMD as well. CONCLUSION Long-term physiological transdermal estradiol replacement in combination with oral medroxyprogesterone acetate restores mean femoral neck BMD to normal in young women with spontaneous 46,XX primary ovarian insufficiency. However, the addition of physiological transdermal T replacement did not provide additional benefit.

Effects of ovarian failure and X-chromosome deletion on body composition and insulin sensitivity in young women.

Objective: Menopause is associated with increased visceral adiposity and reduced insulin sensitivity. It remains unclear whether these changes are due primarily to ovarian failure or aging. The aim of this study was to clarify the impact of ovarian failure on body composition and insulin sensitivity in young women. Design: In a cross-sectional study, we compared main outcome measures (body mass index, body composition by dual-energy x-ray absorptiometry, and insulin sensitivity by Quantitative Insulin Sensitivity Check Index) in three groups: women with 46,XX premature ovarian failure (POF), women with premature ovarian failure associated with 45,X or Turner syndrome (TS), and normal control women (NC). Participants were enrolled in National Institutes of Health Clinical Center protocols between years 2000 and 2005. Results: Mean body mass index (±SD) was lower in women with POF (n = 398): 24.3 ± 5 kg/m2 versus 27.8 ± 7 for women with TS (n = 131) and 26.6 ± 4 for controls (n = 73) (both P < 0.001). Only 33% of women with POF were overweight or obese, compared with 56% of those with TS and 67% of NC women (P < 0.0001 for both). Despite less obesity, women with POF had lower insulin sensitivity (0.367 ± 0.03) compared with those with TS (0.378 ± 0.03, P = 0.003) and NC women (0.376 ± 0.03, P = 0.04). In groups selected for similar age and body mass index, women with POF (n = 89), women with TS (n = 48), and NC women (n = 40) had similar total body and trunk adiposity. After adjustment for age and truncal adiposity, women with POF had significantly lower insulin sensitivity than women with TS (P = 0.03) and NC women (P = 0.049). Conclusions: In contrast to observations in middle-aged postmenopausal women, ovarian failure in young women is not associated with increased total or central adiposity. In fact, women with TS were similar to NC women, whereas women with POF were leaner. The lower insulin sensitivity observed in women with POF deserves further investigation.

A prospective evaluation of antral follicle function in women with 46,XX spontaneous primary ovarian insufficiency

OBJECTIVE To assess ovarian follicle function in women with 46,XX spontaneous primary ovarian insufficiency. DESIGN Case-control with nested prospective cohort. SETTING Clinical Research Center, National Institutes of Health. PATIENT(S) Women with primary ovarian insufficiency without estrogen replacement for 2 weeks (N = 97) and regularly menstruating control women (N = 42). INTERVENTION(S) Single injection of 300 IU hrFSH. MAIN OUTCOME MEASURE(S) Change in serum estradiol at 24 hours. RESULT(S) Antral follicles ≥3 mm were detected in 73% (69/95) of patients; both serum estradiol and progesterone levels correlated significantly with maximum follicle diameter in these women. Patients with a maximum follicle diameter ≥8 mm had significantly higher serum estradiol and progesterone levels and significantly lower FSH and LH levels compared with patients without such follicles. In controls estradiol levels increased significantly after FSH administration, but in patients this was not the case despite the presence of an antral follicle ≥8 mm. CONCLUSION(S) Most women with 46,XX spontaneous primary ovarian insufficiency have antral follicles detectable by ultrasound, suggesting that down-regulation of FSH receptors is not the predominant mechanism of follicle dysfunction. Evidence of progesterone secretion by antral follicles ≥8 mm in these patients is consistent with prior histologic evidence that follicle luteinization is the predominant mechanism of follicle dysfunction in this condition. Prospective controlled investigation designed to improve ovulatory function and fertility in these women is indicated.

Investigation of KIT gene mutations in women with 46,XX spontaneous premature ovarian failure

BackgroundSpontaneous premature ovarian failure presents most commonly with secondary amenorrhea. Young women with the disorder are infertile and experience the symptoms and sequelae of estrogen deficiency. The mechanisms that give rise to spontaneous premature ovarian failure are largely unknown, but many reports suggest a genetic mechanism in some cases. The small family size associated with infertility makes genetic linkage analysis studies extremely difficult. Another approach that has proven successful has been to examine candidate genes based on known genetic phenotypes in other species. Studies in mice have demonstrated that c-kit, a transmembrane tyrosine kinase receptor, plays a critical role in gametogenesis. Here we test the hypothesis that human KIT mutations might be a cause of spontaneous premature ovarian failure.Methods and ResultsWe examined 42 women with spontaneous premature ovarian failure and found partial X monosomy in two of them. In the remaining 40 women with known 46,XX spontaneous premature ovarian failure we evaluated the entire coding region of the KIT gene. We did this using polymerase chain reaction based single-stranded conformational polymorphism analysis and DNA sequencing. We did not identify a single mutation that would alter the amino acid sequence of the c-KIT protein in any of 40 patients (upper 95% confidence limit is 7.2%). We found one silent mutation at codon 798 and two intronic polymorphisms.ConclusionMutations in the coding regions of the KIT gene appear not to be a common cause of 46,XX spontaneous premature ovarian failure in North American women.

Five mutations of mitochondrial DNA polymerase-gamma (POLG) are not a prevalent etiology for spontaneous 46,XX primary ovarian insufficiency

The study objective was to determine if mutations in mitochondrial DNA polymerase gamma (POLG) are associated with spontaneous 46,XX primary ovarian insufficiency (sPOI) using restriction fragment length polymorphism analysis of genomic DNA. Of 201 women with 46,XX sPOI analyzed, we found only one case (0.5%, 95% confidence interval 0-3%) of heterozygosity for a POLG mutation, suggesting that this is not a common genetic etiology for this form of infertility.