The novel peptide PFAP1 promotes primordial follicle activation by binding to MCM5.

Premature ovarian failure (POF) is a complication of ovarian dysfunction resulting from the depletion or dysfunction of primordial follicles (PFs) in the ovaries. However, residual follicles that have the potential to be activated are present in POF or aged women. Little is known about the mechanisms by which the remaining dormant PFs in POF patients are activated. Using mass spectrometry, we screened differentially generated peptides extracted from the ovarian cortical tissue biopsies of patients with or without POF, during which we identified PFAP1, a peptide that significantly promoted the activation of PFs in the ovaries of 3 dpp mice in vitro. PFAP1 reversed age-related fertility damage in vivo to a certain extent, promoted estrogen (E2) and anti-mullerian hormone (AMH) production (p < .05), and decreased the levels of follicle-stimulating hormone (FSH) (p < .05). In newborn mouse ovaries, PFAP1 could bind to the protein minichromosome maintenance protein 5 (MCM5) and inhibit its ubiquitination and degradation. In addition, PFAP1 promoted the proliferation of GCs, probably by regulating the function and production of MCM5. In conclusion, PFAP1 could promote the activation of PFs in the ovaries of newborn mice, partially restore the ovarian function of aged mice, and increase the proliferation of primary granulosa cells (GCs) by regulating the function of MCM5. PFAP1 is a promising novel peptide that may be developed into a new therapeutic agent for POF and other ovarian diseases.

Effects of Low-Intensity Pulsed Ultrasound on the Migration and Homing of Human Amnion-Derived Mesenchymal Stem Cells to Ovaries in Rats With Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) can cause multiple sequelae and is currently incurable. Mesenchymal stem cell (MSC) transplantation might provide an effective treatment method for POI. However, the clinical application of systemic MSC transplantation is limited by the low efficiency of cell homing to target tissue in vivo, including systemic MSC transplantation for POI treatment. Thus, exploration of methods to promote MSC homing is necessary. This study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) on the migration and homing of transplanted human amnion-derived MSCs (hAD-MSCs) to ovaries in rats with chemotherapy-induced POI. For LIPUS treatment, hAD-MSCs were exposed to LIPUS or sham irradiation. Chemokine receptor expressions in hAD-MSCs were detected by polymerase chain reaction (PCR), Western blot, and immunofluorescence assays. hAD-MSC migration was detected by wound healing and transwell migration assays. Cyclophosphamide-induced POI rat models were established to evaluate the effects of LIPUS on the homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in vivo. We found that hAD-MSCs expressed chemokine receptors. The LIPUS promoted the expression of chemokine receptors, especially CXCR4, in hAD-MSCs. SDF-1 induced hAD-MSC migration. The LIPUS promoted hAD-MSC migration induced by SDF-1 through SDF-1/CXCR4 axis. SDF-1 levels significantly increased in ovaries induced by chemotherapy in POI rats. Pretreating hAD-MSCs with LIPUS increased the number of hAD-MSCs homing to ovaries in rats with chemotherapy-induced POI to some extent. However, the difference was not significant. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation reduced ovarian injuries and improved ovarian function in rats with chemotherapy-induced POI. CXCR4 antagonist significantly reduced the number of hAD-MSCs- and LIPUS-pretreated hAD-MSCs homing to POI ovaries, and further reduced their efficacy in POI treatment. According to these findings, pretreating MSCs with LIPUS before transplantation might provide a novel, convenient, and safe technique to explore for improving the homing of systemically transplanted MSCs to target tissue.

Treatment of Urogenital Symptoms in Individuals With a History of Estrogen-dependent Breast Cancer: Clinical Consensus.

SUMMARY: With an estimated 3.8 million breast cancer survivors in the United States, obstetrician-gynecologists often are on the front lines of addressing survivorship issues, including the hypoestrogenic-related adverse effects of cancer therapies or early menopause in survivors (1). Although systemic and vaginal estrogen are used widely for symptomatic relief of genitourinary syndrome of menopause in the general population, among individuals with a history of hormone-sensitive cancer, there is uncertainty about the safety of hormone-based therapy, leading many individuals with bothersome symptoms to remain untreated, with potential negative consequences on quality of life (2). An effective management strategy requires familiarity with a range of both hormonal and nonhormonal treatment options, knowledge about the pharmaceutical mechanisms of action, and the ability to tailor treatment based on individual risk factors. This clinical consensus document was developed using an a priori protocol in conjunction with two authors specializing in urogynecology and gynecologic oncology. This document has been updated to review the safety and efficacy of newer hormonal treatment options as well as nonhormonal modalities.

Association of premature menopause with incident pulmonary hypertension: A cohort study.

BACKGROUND: Several forms of pulmonary hypertension (PH) disproportionately affect women. Animal and human studies suggest that estradiol exerts mixed effects on the pulmonary vasculature. Whether premature menopause represents a risk factor for PH is unknown. METHODS AND FINDINGS: In this cohort study, women in the UK Biobank aged 40-69 years who were postmenopausal and had complete data available on reproductive history were included. Premature menopause, defined as menopause occurring before age 40 years. Postmenopausal women without premature menopause served as the reference group. The primary outcome was incident PH, ascertained by appearance of a qualifying ICD code in the participant's UK Biobank study record. Of 136,715 postmenopausal women included, 5,201 (3.8%) had premature menopause. Participants were followed up for a median of 11.1 (interquartile range 10.5-11.8) years. The primary outcome occurred in 38 women (0.73%) with premature menopause and 409 (0.31%) without. After adjustment for age, race, ever-smoking, body-mass index, systolic blood pressure, antihypertensive medication use, non-high-density lipoprotein cholesterol, cholesterol-lowering medication use, C-reactive protein, prevalent type 2 diabetes, obstructive sleep apnea, heart failure, mitral regurgitation, aortic stenosis, venous thromboembolism, forced vital capacity (FVC), the forced expiratory volume in 1 second-to-FVC ratio, use of menopausal hormone therapy, and hysterectomy status, premature menopause was independently associated with PH (hazard ratio 2.13, 95% CI 1.31-3.23, P<0.001). In analyses of alternate menopausal age thresholds, risk of PH appeared to increase progressively with younger age at menopause (Ptrend <0.001), with 4.8-fold risk in women with menopause before age 30 years (95% CI 1.82-12.74, P = 0.002). Use of menopausal hormone therapy did not modify the association of premature menopause with PH. CONCLUSIONS: Premature menopause may represent an independent risk factor for PH in women. Further investigation of the role of sex hormones in PH is needed in animal and human studies to elucidate pathobiology and identify novel therapeutic targets.

Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol.

BACKGROUND: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment  as the primary outcome in CCS. METHODS: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. DISCUSSION: This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.

Distrofia ósea esclerosante mixta / Mixed-sclerosing-bone-dystrophy

El término "distrofia ósea esclerosante mixta" describe la combinación de las características radiológicas correspondientes a melorreostosis, osteopoiquilosis y osteopatía estriada, como entidades individuales, que ocurren en un mismo paciente. El objetivo de esta comunicación es presentar el caso clínico de una paciente con diagnóstico de distrofia ósea esclerosante mixta y, a partir de este caso, realizar una revisión sobre el tema. (AU)

The term "mixed-sclerosing-bone-dystrophy" describes the combination of the radiological characteristics corresponding to melorheostosis, osteopoikilosis and osteopathia striata, as individual conditions, ocurring in the same patient. The aim of this communication is to present the clinical case of a patient diagnosed with mixed-sclerosing-bone-dystrophy and, based on this case, to undertake a review of this condition. (AU)

Comparison of metabolic profile and abdominal fat distribution between karyotypically normal women with premature ovarian insufficiency and age matched controls.

OBJECTIVE: We designed a prospective case-control study in order to investigate the lipid profiles, insulin sensitivity, presence of metabolic syndrome (MetS) and the abdominal fat distribution in karyotypically normal women with premature ovarian insufficiency (POI). METHODS: Anthropometric measurements, FSH, estradiol, total testosterone (T), sex hormone binding globulin (SHBG), free androgen index (FAI), fasting glucose and insulin, homeostatic model for insulin resistance (HOMA-IR), lipid profile, the prevalence of MetS and ultrasonographic abdominal fat measurements were assessed in 56 women with POI and 59 healthy controls at the same age range. RESULTS: Serum levels of T, SHBG and FAI were not significantly different between both groups. Total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were higher in women with POI. There were no differences in glucose, insulin, HOMA-IR, low-density lipoprotein cholesterol (LDL-C), triglyceride levels between the two groups. A significant positive correlation was identified between T and TG and also between FAI and LDL-C; SHBG levels were correlated inversely with FSH, and positively with HDL-C in women with POI. The presence of MetS was significantly higher in women with POI. The subcutaneous, preperitoneal and visceral fat thicknesses were not significantly different between the groups. CONCLUSIONS: Early cessation of ovulatory function may associated with higher levels of serum TC and HDL-C, but does not seem to cause differences in abdominal fat distribution in women with POI. POI is associated with higher risk of MetS.

Premature menopause and risk of neurological disease: basic mechanisms and clinical implications.

Since basic scientific studies in the 1990s revealed dramatic gender differences in neurological damage from cerebral ischemia, significant evidence has accumulated for a neuroprotective role of ovarian-derived 17ß-Estradiol (E2). Intriguingly, observational studies have further suggested that early and prolonged loss of ovarian E2 (premature menopause) leads to a doubled lifetime risk for dementia and a fivefold increased risk of mortality from neurological disorders, but some controversy remains. Here, we briefly summarize and analyze clinical cohort studies assessing the detrimental neurological outcomes of premature menopause. Furthermore, we discuss current basic science studies elucidating the molecular mechanisms underlying the enhanced risk of neurological disease in prematurely menopausal women and the "window of opportunity" for estrogen benefit. Finally, we highlight four critical issues in the field that require collaboration between basic scientists and clinicians for successful resolution, with the ultimate goal of maintaining optimal neurological health in prematurely menopausal women.

Chemotherapy-induced ovarian toxicity in patients affected by endocrine-responsive early breast cancer.

Cytotoxic chemotherapy may variably affect ovarian function depending on age and ovarian reserve at diagnosis, type of chemotherapy and use of tamoxifen. Ascertaining whether a premenopausal patient with endocrine-responsive early breast cancer and chemotherapy-induced amenorrhea has reached menopause is essential not only in order to provide accurate information on residual fertility, but also to appropriately prescribe endocrine therapy. Indeed, aromatase inhibitors are contraindicated in women with residual ovarian reserve. However, the diagnosis of menopause in patients with chemotherapy-induced amenorrhea is challenging, since clinical features, follicle-stimulating hormone and estradiol levels may be inaccurate to this aim. Recent studies demonstrated that the anti-müllerian hormone may improve the assessment of ovarian reserve residual to chemotherapy in women with early breast cancer. Herein, we review the incidence of amenorrhea and menopause induced by cytotoxic chemotherapy in women affected by early breast cancer and the suggested mechanisms that sustain these side-effects. Furthermore, it has been scrutinized the potential of new markers of ovarian reserve that may facilitate the selection of appropriate endocrine treatment for premenopausal women who develop amenorrhea following adjuvant chemotherapy for early breast cancer.

Comparison of the acute alterations in serum bone turnover markers and bone mineral density among women with surgical menopause.

OBJECTIVE: To determine the effect of a sudden decrease in estrogen levels via bilateral oophorectomy on serum turnover markers and to examine their correlation with bone mineral density (BMD). STUDY DESIGN: This study included 51 women who had regular menses preoperatively and underwent bilateral oophorectomy for benign reasons. These women did not have any systemic disease or drug use that would influence bone metabolism. For each woman, spine and femur BMD were measured preoperatively and sixth months after surgery. Serum C-terminal telopeptide (CTX) and bone alkaline phosphatase (BAP) were measured preoperatively and at the first and sixth months after surgery. Correlations between bone turnover markers and BMD were pre- and post-operatively analyzed. RESULTS: The mean serum CTX and BAP concentrations at the first and sixth postoperative months were significantly higher compared to the preoperative measurements (p=0.001). Spine BMD values at the sixth postoperative month was significantly lower compared to preoperative period (p=0.0001). There was a significant negative correlation between spine BMD values and BAP levels both in the preoperative period and at the sixth postoperative month (r=-0.407, p=0.001), whereas a significant positive correlation between serum CTX and BAP was noted at this time periods (r=0.615, p<0.001). CONCLUSIONS: The results of this study showed that serum BAP and CTX levels rapidly increase in women after bilateral oophorectomy. Therefore, these markers (especially BAP) could be useful in the evaluation of osteoporosis risk in the early period of surgical menopause.

Impact of surgical menopause on lipid and bone metabolism.

OBJECTIVE: To clarify the effects of ovariectomy on lipid and bone metabolism. METHODS: This study was a prospective study with a longitudinal design within 1 year after surgery. Sixty-two premenopausal women were recruited and divided into two groups: group M (preservation of ovary, n=27) and group BSO (bilateral ovariectomy, n=35). Serum lipid levels, urinary N-telopeptide of type I collagen (NTx) and bone mineral density (BMD) were measured. We also examined the number of postoperative episodes requiring pharmacological intervention. RESULTS: There was a significant elevation in the level of low density lipoprotein cholesterol in group BSO from 6 to 12 months compared with the baseline level; the level did not change in group M. The NTx level significantly increased from 6 to 12 months, and the BMD was significantly decreased by as much as 6.7% at 12 months in group BSO; these variables did not change in group M. The effect of lipid and bone metabolism in group BSO was observed when the ages of the two groups were matched. Carbohydrate metabolism and arterial stiffness, measured by pulse wave velocity, did not change throughout the study period in either group. No subjects in group M required medication expect for two patients whose ovarian function was diminished by postoperative radiation and by natural menopause. Eleven women received medication in group BSO: nine for climacteric disorders using hormone therapy (25.7%), and two for dyslipidemia using statins (5.7%). CONCLUSIONS: Bilateral ovariectomy seems to cause dyslipidemia and serious loss of bone mineral density within only 1 year, and patients who lose ovarian function may require careful medical care.

S-equol and the fermented soy product SE5-OH containing S-equol similarly decrease ovariectomy-induced increase in rat tail skin temperature in an animal model of hot flushes.

OBJECTIVE: The aim of this study was to compare the effect of SE5-OH, a fermented soy product containing S-equol, with purified S-equol on hot flushes in an ovariectomized rat model. METHODS: Eleven-week-old female Sprague-Dawley rats were assigned to either the sham group (vehicle; n = 30) or one of four ovariectomized groups: control (vehicle; n = 30), conjugated equine estrogens (CEE; 6.0 mg kg(-1) d(-1) CEE; n = 10), SE5-OH (2,000 mg kg(-1) d(-1) SE5-OH containing 11.7 mg kg(-1) d(-1) as S-equol; n = 30), and S-equol (11.7 mg kg(-1) d(_1) S-equol; n = 30). Three days after sham operation or ovariectomy, animals were treated once daily for 38 days. Tail skin temperature (TST) was assessed on days 21, 28, and 35 after surgery. Plasma estradiol and follicle-stimulating hormone levels and uterine weight and uteri histology were evaluated at the end of treatment. RESULTS: The rise in TST resulting from ovariectomy was inhibited by CEE, SE5-OH, and S-equol. Compared with the control, TST was decreased by 68.9% and 86.2% in SE5-OH group on days 21 and 28, respectively (P = 0.014, 0.020), and by 60.1% and 89.1% in S-equol group, respectively (P = 0.038, 0.016). Unlike in the CEE group, plasma estradiol and follicle-stimulating hormone levels, uterine weight, epithelial height, stromal expansion, and myometrial thickness were not affected in SE5-OH and S-equol groups. CONCLUSIONS: The results of this animal model of hot flushes suggest that S-equol is one of the primary components of SE5-OH and that both SE5-OH and S-equol represent promising alternatives for the treatment of menopausal symptoms. Clinical research is needed to confirm these findings.

Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.

OBJECTIVE: There is increasing laboratory evidence for a neuroprotective effect of estrogen; however, the clinical and epidemiologic evidence remains limited and conflicting. We studied the association of oophorectomy performed before the onset of menopause with the risk of subsequent cognitive impairment or dementia. METHODS: We included all women who underwent unilateral or bilateral oophorectomy before the onset of menopause for a non-cancer indication while residing in Olmsted County, MN, from 1950 through 1987. Each member of the oophorectomy cohort was matched by age to a referent woman from the same population who had not undergone oophorectomy. In total, we studied 813 women with unilateral oophorectomy, 676 women with bilateral oophorectomy, and 1,472 referent women. Women were followed through death or end of study using either direct or proxy interviews. RESULTS: Women who underwent either unilateral or bilateral oophorectomy before the onset of menopause had an increased risk of cognitive impairment or dementia compared to referent women (hazard ratio [HR] = 1.46; 95% CI 1.13 to 1.90; adjusted for education, type of interview, and history of depression). The risk increased with younger age at oophorectomy (test for linear trend; adjusted p < 0.0001). These associations were similar regardless of the indication for the oophorectomy, and for women who underwent unilateral or bilateral oophorectomy considered separately. CONCLUSIONS: Both unilateral and bilateral oophorectomy preceding the onset of menopause are associated with an increased risk of cognitive impairment or dementia. The effect is age-dependent and suggests a critical age window for neuroprotection.

Implications for estrogens in Parkinson's disease: an epidemiological approach.

Evidence from experimental and epidemiological studies suggests a role of sex hormones in the pathogenic process leading to neurodegenerative diseases, (i.e., Alzheimer's and Parkinson's disease). The effects of sexual steroid hormones are complex and vary with the events of women's fertile life. Estrogens are supposed to influence dopamine synthesis, metabolism, and transport; however, there is no consensus regarding the direction, locus, and mechanism of the effect of estrogens on the dopaminergic system. A neuroprotective effect of estrogens has been demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal models of Parkinson's disease (PD). Epidemiological studies indicate gender differences regarding the onset and the prognosis of PD. Most of the analytical studies explored the relationship between PD and exogenous estrogens. Only three studies investigated the role of endogenous estrogens in the risk of developing PD. These studies reported an increased risk of PD in conditions causing an early reduction in endogenous estrogens (early menopause, reduced fertile life length). Longer cumulative length of pregnancies has also been associated with an increased PD risk. A lack of consensus still exists on the effect of the type of menopause (surgical vs. natural) on PD risk. Finally, the effect of postmenopausal estrogen replacement therapy is still debated. Inconsistencies across studies are in part explained by the complexity of the mechanisms of action of sexual hormones and by the paucity of analytical studies.

Background factors influencing somatic and psychological symptoms in middle-age women with different hormonal status. A population-based study of Swedish women.

OBJECTIVE: To analyse the influence of socio-demographic characteristics and environmental factors on self-reported somatic and psychological symptoms among middle-aged Swedish women. METHODS: A total of 6917 women living in the Lund area of southern Sweden were participates of this study. They completed a generic questionnaire pertaining to socio-demographic characteristics, lifestyle factors and current health related problems. According to hormonal status, the participants were subdivided into three groups, i.e. premenopause, postmenopause and peri- or postmenopausal women with hormone replacement therapy (HRT). RESULTS: By using multiple logistic regression models, a high risk for somatic symptoms was independently associated with unemployment, no exercise, unmarried, high body weight and diseases affecting the cardiovascular system as well as a history of cancer. Psychological symptoms were independently associated with higher educational level, unemployment, no exercise, unmarried, heavy smoking habits (> or =15 cig/day), weight gain and a history of cancer. In addition, the background factors seemed to have less impact on symptoms among women who used HRT. CONCLUSION: Socio-demographic characteristics, lifestyle factors and concurrent health problems appear to have influences on the frequency and the number of somatic and psychological symptoms in middle-age women. Hormone replacement therapy seems to be able to counteract negative impacts caused by un-healthy lifestyle and other health problems.

Chemotherapy-induced ovarian failure: manifestations and management.

Thanks to improvements in treatment regimens, more and more patients are now surviving cancer. However, cancer survivors are faced with the serious long-term effects of the different modalities of cancer treatments. One of these adverse effects is chemotherapy-induced irreversible damage to the ovarian tissues, which leads to premature ovarian failure and its resulting consequences such as hot flashes, osteoporosis, sexual dysfunction and the risk of infertility. Chemotherapy-induced ovarian failure (or chemotherapy-induced premature menopause) affects the quality of life of female cancer survivors. Although there is no clear definition of chemotherapy-induced ovarian failure, irreversible amenorrhoea lasting for several months (>12 months) following chemotherapy and a follicle stimulating hormone level of > or = 30 MIU/mL in the presence of a negative pregnancy test seems to be an appropriate characterisation. Different chemotherapy agents, alkylating cytotoxics in particular, have the potential to cause progressive and irreversible damage to the ovaries. The result of this damage is a state of premature ovarian failure, with progressive declining of estrogen levels, decreasing bone mass and an increased risk of fractures. Historically, hormonal replacement therapy (HRT) has been used to treat menopausal problems in the general population, but concerns about the potential of estrogen to increase the risk of breast cancer in women at high-risk or increase the risk of recurrence in cancer survivors, have forced physicians to utilise alternative treatments. This review discusses some of the newer therapies that are now available to provide appropriate symptom control, avoid complications such as fractures and possibly prevent infertility by making the ovarian epithelium less susceptible to cytotoxic agents.

Managing the risk of osteoporosis in women with a history of early breast cancer.

Estrogen is known to play an important role in skeletal health. Female breast cancer patients who receive treatments that reduce estrogen levels, such as aromatase inhibitors, may increase their risk of developing osteoporosis and their risk of fracture. Clinical guidelines enable the physician to assess the risk of osteoporosis by patient history and physical examination. For patients identified as being at risk, it is necessary to test bone mineral density (BMD), using the result to determine which patients require treatment. Two groups can be identified as requiring BMD assessment according to general guidelines: patients < 45 years old who become menopausal due to treatment, and breast cancer patients receiving aromatase inhibitors. Bisphosphonates appear to be the logical treatment of choice for breast cancer patients, as they do not interact with the estrogen receptor. Although not all women receiving aromatase inhibitors will require additional treatment for bone health, postmenopausal women with a history of breast cancer at risk of osteoporosis should be identified, monitored, and managed according to practice guidelines.

Bone mineralization in women following successful treatment of Hodgkin's disease.

PURPOSE: Women with Hodgkin's disease in whom a cure has been achieved may be at risk for osteoporosis because of therapy-induced premature menopause. Our objective was to gather information regarding the integrity of bone mass in such long-term cancer survivors. SUBJECTS AND METHODS: Bone mineral density was measured using photon absorptiometry in five groups of women: 11 patients with Hodgkin's disease and ovarian failure (Group I); six patients with Hodgkin's disease and ovarian failure who received estrogen replacement (Group II); 15 patients with Hodgkin's disease and normal ovarian function (Group III); 16 premenopausal control subjects (Group IV); and 11 postmenopausal control subjects (Group V). All patients with Hodgkin's disease were in remission and had completed treatment more than five years earlier. RESULTS: Subjects in Group I were found to have significantly decreased radial (p = 0.0009), lumbar spine (p = 0.002), and femoral neck (p = 0.0001) bone mineral density measurements compared with those in subjects in Group IV; the bone mineral density measurements at all sites of subjects in Group I were no different than those of subjects in Group V. Subjects in Group III had bone density measurements that were similar to those in Group IV, although the radial bone mineral density value was significantly lower (p = 0.0004). Determination of serum gonadotropins and estradiol was consistent with the menstrual status defining the five groups. No secondary causes for decreased bone mineral density values could be detected, since the mean serum levels of parathyroid hormone, calcium, phosphorus, and vitamin D metabolites were similar among the groups, and all prolactin levels were normal. CONCLUSION: We have identified a new population of patients with a high risk of osteoporosis, and these results emphasize the importance of treatment-related ovarian failure in the pathogenesis of osteoporosis.