The Journal of Clinical Endocrinology & Metabolism

Breast Cancer Is Increased in Women With Primary Ovarian Insufficiency

Abstract Context DNA damage/repair gene variants are associated with both primary ovarian insufficiency (POI) and cancer risk. Objective We hypothesized that a subset of women with POI and family members would have increased risk for cancer. Design Case-control population-based study using records from 1995 to 2022. Setting Two major Utah academic health care systems serving 85% of the state. Subjects Women with POI (n = 613) were identified using International Classification of Diseases codes and reviewed for accuracy. Relatives were linked using the Utah Population Database. Intervention Cancer diagnoses were identified using the Utah Cancer Registry. Main Outcome Measures The relative risk of cancer in women with POI and relatives was estimated by comparison to population rates. Whole genome sequencing was performed on a subset of women. Results Breast cancer was increased in women with POI (OR, 2.20; 95% CI, 1.30-3.47; P = .0023) and there was a nominally significant increase in ovarian cancer. Probands with POI were 36.5 ± 4.3 years and 59.5 ± 12.7 years when diagnosed with POI and cancer, respectively. Causal and candidate gene variants for cancer and POI were identified. Among second-degree relatives of these women, there was an increased risk of breast (OR, 1.28; 95% CI, 1.08-1.52; P = .0078) and colon cancer (OR, 1.50; 95% CI, 1.14-1.94; P = .0036). Prostate cancer was increased in first- (OR, 1.64; 95% CI, 1.18-2.23; P = .0026), second- (OR, 1.54; 95% CI, 1.32-1.79; P < .001), and third-degree relatives (OR, 1.33; 95% CI, 1.20-1.48; P < .001). Conclusion Data suggest common genetic risk for POI and reproductive cancers. Tools are needed to predict cancer risk in women with POI and potentially to counsel about risks of hormone replacement therapy.

Cardiometabolic Effects of Denosumab in Premenopausal Women With Breast Cancer Receiving Estradiol Suppression: RCT

Abstract Context Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects of estradiol suppression and has been reported to have effects on body composition and metabolic parameters in preclinical and observational studies, but evidence from double-blind randomized controlled trials is limited. Objective To assess the effect of denosumab on body composition and metabolic parameters. Methods In a prespecified secondary analysis of a 12-month randomized, double-blind, placebo-controlled trial, 68 premenopausal women with breast cancer initiating ovarian function suppression and aromatase inhibition were randomized to denosumab 60-mg or placebo administered at baseline and 6 months. Outcome measures were total and regional fat and lean mass (DXA), body mass index (BMI), waist and hip circumference, fasting glucose, HOMA-IR, and lipid profile. Using a mixed model, between-group mean adjusted differences over time are reported. Results Over 12 months, relative to placebo, android and gynoid fat mass decreased in the denosumab group (−266 g [95% CI −453 to −79], P = .02, and −452 g [−783 to −122], P = .03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly (−1792 g [−3346 to −240], P = .08 and (− 3.77 cm [−6.76 to −0.79], P = .06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile. Conclusion In premenopausal women receiving estradiol suppression, denosumab decreases some measures of fat mass with no detectable effects on other measures of body composition or metabolic parameters.

WHAM—A Prospective Study of Weight and Body Composition After Risk-Reducing Bilateral Salpingo-oophorectomy

Abstract Context Body weight and composition may change over the natural menopause transition. Whether surgical menopause has similar effects, and the impact of hormone replacement therapy (HRT), are unknown. Understanding the metabolic effects of surgical menopause will inform clinical care. Objective To prospectively measure weight and body composition over 24 months following surgical menopause compared with a similar comparison group who retained their ovaries. Methods Prospective observational study of weight change from baseline to 24 months in 95 premenopausal women at elevated risk of ovarian cancer planning risk-reducing salpingo-oophorectomy (RRSO) and 99 comparators who retained their ovaries. Change in body composition from baseline to 24 months was also assessed by dual-energy x-ray absorptiometry in a subgroup of 54 women who underwent RRSO and 81 comparators who retained their ovaries. In the subgroup, weight, fat mass, lean mass, and abdominal fat measures were compared between groups. Results At 24 months both groups had gained weight (RRSO 2760 ± 4860 g vs comparators 1620 ± 4540 g) with no difference between groups (mean difference 730 g; 95% CI 920 g to 2380 g; P = .383). In the body composition subgroup, there was no difference in weight between groups at 24 months (mean difference 944 g; 95% CI −1120 g to 2614 g; P = .431). RRSO women may have gained slightly more abdominal visceral adipose tissue (mean difference 99.0 g; 95% CI 8.8 g to 189.2 g; P = .032) but there were no other differences in body composition. There were also no differences in weight or body composition between HRT users and nonusers at 24 months. Conclusion 24 months after RRSO, there was no difference in body weight compared with women who retained their ovaries. RRSO women gained more abdominal visceral adipose tissue than comparators, but there were no other differences in body composition. Use of HRT following RRSO had no effect on these outcomes.

Serum Estradiol and 20 Site-Specific Cancers in Women: Mendelian Randomization Study

AbstractContextThe causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear.ObjectiveThis Mendelian randomization study assessed the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women.MethodsAs primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio.ResultsGenetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor (ER)-positive breast cancer (OR 1.02; 95% CI, 1.01-1.03; P = 2.5 × 10−3), endometrial cancer overall (OR 1.09; 95% CI, 1.06-1.11; P = 7.3 × 10−13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI, 1.07-1.13; P = 2.1 × 10−11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI, 1.00-1.02; P = 0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI, 1.01-1.10; P = 0.02), and stomach cancer (OR 1.12; 95% CI, 1.00-1.26; P = 0.05), but no significant association with other cancers.ConclusionThis study supports a role of E2 in the development of ER-positive breast cancer and endometrioid endometrial cancer but found no strong association with other cancers in women.

Economic Burden of Endometrial Cancer Associated With Polycystic Ovary Syndrome

Abstract Context Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged females, and women with PCOS are at increased risk for endometrial cancer (EndoCA), the most common gynecological malignancy. Objective Our study sought to assess the economic burden associated with EndoCA in PCOS. Method Using PRISMA systematic review guidelines, we evaluated studies on EndoCA rates in patients with PCOS. Excluded studies were reviews and case reports, those with nonhuman subjects, without controls, without full text available, or reporting solely on other conditions. Selected studies were assessed for quality using the Newcastle-Ottawa Scale. Meta-analysis used DerSimonian-Laird random effects model to assess pooled risk ratio (RR). Excess cost was assessed in US dollars (USD). Result Of 98 studies screened, 9 were included. Pooled RR for EndoCA in PCOS was 3.46 (95% CI, 2.28-5.23), P ≤ .001. In the United States, prevalence of EndoCA in patients with PCOS in 2020 was 1.712%, compared with a baseline estimated prevalence in all women of 0.489%. The excess prevalence of EndoCA attributable to PCOS was 1.223%, approximately 98 348 affected women. A population attributable fraction of EndoCA for PCOS was 24.4%. Given estimated costs of EndoCA exceeding $1.9 billion (in 2023 USD), the economic burden of EndoCA attributable to PCOS exceeds $467 million/year. Conclusion The excess annual US healthcare cost for EndoCA attributable to PCOS exceeds $467 million/year (2023 USD). Although a concerning morbidity of PCOS, it is notable that the economic burden of EndoCA attributable to the disorder represents only a small fraction of its total healthcare burden.

11C-Metomidate PET/CT Detected Multiple Ectopic Adrenal Rest Tumors in a Woman With Congenital Adrenal Hyperplasia

Abstract Context Women with congenital adrenal hyperplasia (CAH) may present with androgen excess that is difficult to control with conventional suppressive doses of glucocorticoids. Clinical management is challenging, and the woman is at great risk of developing steroid-induced complications. Patients and Methods A 32-year-old woman with salt-wasting CAH due to 21-hydroxylase deficiency underwent right-sided adrenalectomy because of a large myelolipoma. Over the years, androgens became increasingly difficult to suppress on prednisolone 5 + 0 + 2.5 mg daily, and at age 39 years the left adrenal with an enlarging myelolipoma was removed. A month later serum testosterone levels had increased from 4.1 preoperatively to 18.3 nmol/L (reference 0.2-1.8 nmol/L), and adrenocorticotropin levels from 32 to 283 pmol/L (reference < 14 pmol/L). No adrenal parenchyma was visualized on computed tomography (CT). In the further search for the source of the markedly elevated testosterone, positron emission tomography (PET) was performed with 2 different tracers, 18fluorodeoxyglucose (18FDG) reflecting glucose metabolism and 11C-metomidate, an inhibitor of 11-β-hydroxylase targeting adrenocortical tissue. Results 18FDG-PET/CT with cosyntropin stimulation showed ovarian/paraovarian hypermetabolism, suggestive of adrenal rest tumors. Further characterization with 11C-metomidate PET/CT showed uptakes localized to the ovaries/adnexa, behind the spleen, and between the right crus diaphragmaticus and inferior vena cava. Conclusion Adrenal rest tumors can give rise to high androgen levels in spite of suppressive supraphysiological glucocorticoid doses. This case illustrates, for the first time, the value of 11C-metomidate PET as a sensitive method in documenting adrenal rest tumors, currently considered rare in women with CAH.

Causes and Consequences of Polycystic Ovary Syndrome: Insights From Mendelian Randomization

Abstract Context Although polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age, risk factors that may cause the syndrome are poorly understood. Based on epidemiologic studies, PCOS is thought to cause several adverse outcomes such as cardiovascular disease; however, the common presence of comorbidities such as obesity may be responsible for such associations, rather than PCOS in and of itself. To overcome the limitations of observational studies, investigators have employed Mendelian randomization (MR), which uses genetic variants to interrogate causality between exposures and outcomes. Evidence Acquisition To clarify causes and consequences of PCOS, this review will describe MR studies involving PCOS, both as an exposure and as an outcome. The literature was searched using the terms “Mendelian randomization,” “polycystic ovary syndrome,” “polycystic ovarian syndrome,” and “PCOS” (to May 2021). Evidence Synthesis MR studies have suggested that obesity, testosterone levels, fasting insulin, serum sex hormone-binding globulin concentrations, menopause timing, male-pattern balding, and depression may play a causal role in PCOS. In turn, PCOS may increase the risk of estrogen receptor–positive breast cancer, decrease the risk of endometrioid ovarian cancer, and have no direct causal effect on type 2 diabetes, coronary heart disease, or stroke. Conclusions The accumulation of genome-wide association studies in PCOS has enabled multiple MR analyses identifying factors that may cause PCOS or be caused by PCOS. This knowledge will be critical to future development of measures to prevent PCOS in girls at risk as well as prevent complications in those who have PCOS.

The Late Effects of Hematopoietic Stem Cell Transplants in Pediatric Patients: A 25-Year Review

Abstract Context A rare, large, single-center study covering all long-term health outcomes of pediatric allogeneic hemopoietic stem cell transplant (HSCT) survivors, to provide comprehensive local data and identify gaps and future directions for improved care. Objective To document endocrine sequelae and other late effects of all HSCT recipients. Design Retrospective review. Setting Royal Children's Hospital Melbourne. Patients 384 children and adolescents received HSCT; 228 formed the study cohort; 212 were alive at commencement of data accrual. Intervention None. Main Outcome Measures Incidence of endocrinopathies; fertility, growth, bone and metabolic status; subsequent malignant neoplasms (SMNs). Results Gonadotoxicity was more common in females (P < .001). Total body irradiation (TBI) conditioning was more toxic than chemotherapy alone. All females receiving TBI or higher cyclophosphamide equivalent doses developed premature ovarian insufficiency. In males, impaired spermatogenesis +/- testicular endocrine dysfunction was associated with increasing testicular radiation exposure. Preservation of gonadal function was associated with younger age at HSCT. Of sexually active females, 22% reported spontaneous pregnancies. Short stature was common, with GH axis disruption in 30% of these. Of patients exposed to thyroid radiation, 51% developed nodules; 30% were malignant. Metabolic disturbances included hypertension and dyslipidemias, with both excess and underweight reported. Fragility fractures occurred in 6% and avascular necrosis in 6%. Thirteen percent developed SMNs, with the risk continuing to rise throughout follow-up. Conclusion We confirm gonadal dysfunction, multiple endocrine and metabolic abnormalities, thyroid cancer, and SMNs as common sequelae of HSCT and identify gaps in management—particularly the need for informed fertility counseling and pretreatment fertility preservation, evaluation, and management of bone health—and underline the need for early lifestyle modification, long-term surveillance, and prospective planned studies aimed at reducing complication risk.

Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated With Polycystic Ovarian Syndrome

AbstractContextPolycystic ovary syndrome (PCOS) is a prevalent disorder in reproductive aged women associated with a number of endocrine and metabolic complications, including increased risk of endometrial cancer.ObjectiveTo study the effect of the characteristic increased androgen levels in PCOS on the endometrium, a novel scaffold-free multicellular endometrial organoid was established.DesignHuman endometrial organoids were constructed using primary endometrial epithelial and stromal cells from endometrial tissues. Organoids were treated for 14 days with physiologic levels of estradiol and testosterone to mimic a normal follicular phase or PCOS hormone profiles. Organoids were harvested for immunostaining and ribonucleic acid sequencing.SettingAcademic institution.PatientsEndometrial tissues from 10 premenopausal women undergoing hysterectomy for benign pathologies were obtained following written consent.Main Outcome MeasuresOrganoid architecture, cell specific markers, functional markers, proliferation, and gene expression were measured.ResultsA method to generate scaffold-free endometrial organoids containing epithelial and stromal cells was established. These organoids exhibited distinct organization with epithelial cells lining the outer surface and stromal cells in the center of the organoids. Epithelial cells were polarized, organoids expressed cell type specific and functional markers, as well as androgen, estrogen, and progesterone receptors. Treatment with PCOS hormones increased cell proliferation and dysregulated genes in endometrial organoids.ConclusionsA new multicellular, scaffold-free endometrial organoid system was established that resembled physiology of the native endometrium. Excess androgens in PCOS promoted cell proliferation in endometrial organoids, revealing new mechanisms of PCOS-associated with risk of endometrial neoplasia.

Progesterone Receptors Promote Quiescence and Ovarian Cancer Cell Phenotypes via DREAM in p53-Mutant Fallopian Tube Models

AbstractContextThe ability of ovarian steroids to modify ovarian cancer (OC) risk remains controversial. Progesterone is considered to be protective; recent studies indicate no effect or enhanced OC risk. Knowledge of progesterone receptor (PR) signaling during altered physiology that typifies OC development is limited.ObjectiveThis study defines PR-driven oncogenic signaling mechanisms in p53-mutant human fallopian tube epithelia (hFTE), a precursor of the most aggressive OC subtype.MethodsPR expression in clinical samples of serous tubal intraepithelial carcinoma (STIC) lesions and high-grade serous OC (HGSC) tumors was analyzed. Novel PR-A and PR-B isoform-expressing hFTE models were characterized for gene expression and cell cycle progression, emboli formation, and invasion. PR regulation of the DREAM quiescence complex and DYRK1 kinases was established.ResultsSTICs and HGSC express abundant activated phospho-PR. Progestin promoted reversible hFTE cell cycle arrest, spheroid formation, and invasion. RNAseq/biochemical studies revealed potent ligand-independent/-dependent PR actions, progestin-induced regulation of the DREAM quiescence complex, and cell cycle target genes through enhanced complex formation and chromatin recruitment. Disruption of DREAM/DYRK1s by pharmacological inhibition, HPV E6/E7 expression, or DYRK1A/B depletion blocked progestin-induced cell arrest and attenuated PR-driven gene expression and associated OC phenotypes.ConclusionActivated PRs support quiescence and pro-survival/pro-dissemination cell behaviors that may contribute to early HGSC progression. Our data support an alternative perspective on the tenet that progesterone always confers protection against OC. STICs can reside undetected for decades prior to invasive disease; our studies reveal clinical opportunities to prevent the ultimate development of HGSC by targeting PRs, DREAM, and/or DYRKs.

Increased HSD11β1 Expression in Human Leiomyomatous Uteri: Implication for Enhanced Glucocorticoid Signaling

Abstract Context FK506-binding-protein-51 (FKBP51) is a glucocorticoid-induced co-chaperone protein previously shown to bind glucocorticoid receptor (GR), inhibiting its transcriptional activity. We previously found increased FKBP51 levels in uterine leiomyoma vs paired myometrium. Objective To test the hypothesis that elevated FKBP51 levels contribute to leiomyoma pathogenesis by altering GR signaling. Design RNA-sequencing was performed in leiomyoma cell cultures transfected with scramble or FKBP5-siRNA for 48 hours, then treated with vehicle or dexamethasone (DEX) for 24 hours. Differentially expressed genes, including HSD11B1, CNN1, and LAMA2 were analyzed by quantitative polymerase chain reaction. Hydroxysteroid 11-β dehydrogenase 1 (HSD11β1) expression was analyzed in leiomyoma, leiomyoma-adjacent paired myometrium, myometrium from patients without leiomyoma, and human endometrial stromal cells by quantitative polymerase chain reaction and immunohistochemistry. Setting University research institution. Patients Women with or without uterine leiomyoma. Main Outcome Measures HSD11B1 mRNA and protein levels in leiomyoma, paired myometrium, and normal myometrium. Results HSD11β1 expression was higher in paired myometrial and leiomyoma tissues vs normal myometrium (P < .02). DEX treatment increased HSD11B1 transcription in normal myometrial and human endometrial stromal cell cultures, but to a significantly greater extent in leiomyoma (P < .001). However, FKBP5-silencing blunted this DEX-induced HSD11B1 upregulation. DEX-treatment reduced LAMA2 and increased CNN1 levels (coding for extracellular matrix and smooth muscle proteins, respectively) in FKBP5-silenced vs scramble siRNA-transfected leiomyoma cultures. Conclusion FKBP51 not only inhibits but can augment GR-mediated transcription. Importantly, FKBP51-GR interactions increase HSD11B1 levels in leiomyoma cells, generating a pathological FKBP51-GR-HSD11β1 circle, altering transcription of downstream extracellular matrix and smooth muscle genes to induce a myofibroblast phenotype, thereby possibly contributing to leiomyoma pathogenesis.

Body Mass Index and Uterine Fibroid Development: A Prospective Study

Abstract Objective Fibroids are hormonally dependent uterine tumors. The literature on adiposity and fibroid prevalence is inconsistent. Previous work usually combined all those with a body mass index (BMI) ≥30 kg/m2 into a single category and relied on clinically diagnosed fibroids, which misclassifies the many women with undiagnosed fibroids. We used a prospective cohort design with periodic ultrasound screening to investigate associations between repeated measures of BMI and fibroid incidence and growth assessed at each follow-up ultrasound. Methods The Study of Environment, Lifestyle & Fibroids followed 1693 Black/African American women, ages 23 to 35 years from Detroit, Michigan, with ultrasound every 20 months for 5 years. Measured height and repeated weight measures were used to calculate BMI. Fibroid incidence was modeled using Cox models among those who were fibroid free at the enrollment ultrasound. Fibroid growth was estimated for individual fibroids matched across visits as the difference in log-volume between visits and was modeled using linear mixed models. All models used time-varying BMI and adjusted for time-varying covariates. Results Compared with BMI <25 kg/m2, those with BMI 30 to <35 kg/m2 had increased fibroid incidence (adjusted hazard ratio, 1.37; 95% CI, 0.96-1.94), those with BMI ≥40 kg/m2 had reduced incidence (adjusted hazard ratio, 0.61; 95% CI, 0.41-0.90). Fibroid growth had mostly small magnitude associations with BMI. Conclusion BMI has a nonlinear association with fibroid incidence, which could be driven by effects of BMI on inflammation and reproductive hormones. More detailed measures of visceral and subcutaneous adiposity and their effects on hormones, DNA damage, and cell death are needed.

Diabetes and Uterine Fibroid Diagnosis in Midlife: Study of Women's Health Across the Nation (SWAN)

Abstract Context Fibroids are noncancerous uterine tumors potentially associated with cardiovascular risk factors. Objective We aimed to examine prospectively associations of glucose, insulin, sex hormone–binding globulin (SHBG), and diabetes with incidence of fibroid diagnoses in midlife. Methods Participants in the Study of Women's Health Across the Nation (SWAN) cohort (n = 2570) reported fibroid diagnoses at enrollment (1996-1997) and 13 follow-up visits (1996-2013). At all visits, we measured glucose, insulin, and SHBG in fasting blood samples and calculated homeostatic model assessment for insulin resistance (HOMA-IR). Diabetes was defined using glucose levels, self-reported diabetes, or diabetes medication use. We used discrete-time survival models to estimate hazard ratios (HR) and 95% CI for associations of time-varying biomarkers and diabetes with incident fibroid diagnoses, adjusted for demographics and health care utilization. We also evaluated effect modification by menopausal status. Results At baseline, 2.7% of participants (n = 70) were using diabetes medication. Time-varying glucose, insulin, HOMA-IR, and SHBG were not associated with fibroid diagnosis. However, diabetes was associated with a 28% lower incidence of fibroid diagnosis (adjusted HR 0.72, 95% CI 0.44, 1.17), driven by participants using metformin (adjusted HR 0.49, 95% CI 0.21, 1.12), though precision was limited. After stratification by menopausal status, higher HOMA-IR and insulin were associated with greater incidence of fibroid diagnosis during premenopause but not perimenopause, while the inverse association between diabetes and fibroids was strongest during perimenopause. Conclusion The effect of diabetes and biomarkers on fibroids may vary by menopausal status. Fibroid risk may increase with insulin resistance and decrease with diabetes treatment.

Then and Now: What We Have Learned From the WHI

Abstract Context This narrative review aims to highlight key learning points from the Women's Health Initiative (WHI) studies, providing a nuanced appraisal of menopausal hormone therapy (MHT) risks and benefits in postmenopausal women. Methods A structured PubMed search was conducted using MeSH terms and keywords for MHT, bone health, cardiovascular and metabolic disease, cancer (breast, endometrial, ovarian, colorectal), and cognitive outcomes. The search included clinical trials, observational studies, and systematic reviews published in the English language. Results WHI data reveal that both combined conjugated equine estrogen-medroxyprogesterone acetate (CEE-MPA) and CEE-only therapy significantly reduce hip, vertebral, and total fracture risk, with further skeletal protection from calcium and vitamin D co-administration. Cardiovascular outcomes are strongly influenced by timing: initiation before age 60 or within 10 years of menopause may confer benefit, while delayed initiation (≥65 years) increases risks of coronary events and stroke, supporting the “window of opportunity” hypothesis. CEE-MPA therapy increases invasive breast cancer incidence (especially in prior users), while estrogen-only therapy is associated with a marginal nonsignificant reduction in breast cancer risk. Both regimens lowered colorectal cancer incidence during active treatment. Early MHT initiation has no effect on cognitive function, whereas late initiation increases dementia risk. Conclusion WHI findings underscore the importance of individualized, time-sensitive MHT use, with benefits and risks shaped by formulation, timing, and patient characteristics. These insights continue to inform evolving clinical practice.