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• W2559178581 abstract "Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women. Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/12358-22846 Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/12358-22846 Primary ovarian insufficiency (POI) is a rare but important cause of sex steroid deficiency and infertility in premenopausal women. POI is characterized by menopausal levels of FSH and absent or irregular menstrual cycles before the age of 40 years. Because the average age of natural menopause is 50–51 years, women exhibiting these findings after age 40 but before age 45 are said to have early menopause (1Nelson L.M. Clinical practice. Primary ovarian insufficiency.N Engl J Med. 2009; 360: 606-614Crossref PubMed Google Scholar). Spontaneous POI affects ∼1% of women before age 40, and ∼0.1% of women before age 30 years. An estimated 5% of women undergo early menopause before the age of 45 years (2Coulam C.B. Adamson S.C. Annegers J.F. Incidence of premature ovarian failure.Obstet Gynecol. 1986; 67: 604-606PubMed Google Scholar). Many of the health complications associated with POI are directly related to ovarian hormone deficiency, primarily estrogen deficiency. This underscores the importance of physiologic hormone replacement therapy (HRT) in women with POI. Unfortunately, data regarding adverse effects from the Women's Health Initiative (WHI) trial, a study of older postmenopausal women, has dissuaded many from using estrogen therapy or estrogen/progestin therapy (EPT) in young women with POI or early menopause (3Sprague B.L. Trentham-Dietz A. Cronin K.A. A sustained decline in postmenopausal hormone use: results from the National Health and Nutrition Examination Survey, 1999–2010.Obstet Gynecol. 2012; 120: 595-603Crossref PubMed Scopus (0) Google Scholar). The WHI showed multiple increased health risks related to the use of EPT, including increased risks of stroke, breast cancer, and cardiovascular disease (CVD) (4Rossouw J.E. Anderson G.L. Prentice R.L. LaCroix A.Z. Kooperberg C. Stefanick M.L. et al.Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Google Scholar). This is unfortunate, because, in contrast to women with normal menopause, the situation in young women with POI and early menopause is in fact a pathologic state of estrogen deficiency compared with their peers with normal ovarian function. In women with POI and early menopause, the term hormone replacement therapy is entirely accurate, because the prescribed hormones are replacing hormones that would normally be present. Health complications of POI include menopausal symptoms (hot flashes, night sweats, insomnia, dyspareunia, decreased sexual desire, and vaginal dryness), decreased bone mineral density (BMD) and increased risk of fracture, infertility, increased risk of mood disorders, namely, depression and anxiety, cognitive decline, sexual dysfunction, increased rates of autoimmune disease, increased risk of cardiovascular disease, increased risk of type 2 diabetes mellitus (T2DM) or pre-DM, and dry eye syndrome (1Nelson L.M. Clinical practice. Primary ovarian insufficiency.N Engl J Med. 2009; 360: 606-614Crossref PubMed Google Scholar). Physiologic EPT ameliorates many of these health risks and is considered standard of care for women with POI or early menopause (1Nelson L.M. Clinical practice. Primary ovarian insufficiency.N Engl J Med. 2009; 360: 606-614Crossref PubMed Google Scholar, 5Stuenkel C.A. Davis S.R. Gompel A. Lumsden M.A. Murad M.H. Pinkerton J.V. et al.Treatment of symptoms of the menopause: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2015; 100: 3975-4011Crossref PubMed Scopus (0) Google Scholar, 6Neves E.C.M. Birkhauser M. Samsioe G. Lambrinoudaki I. Palacios S. Borrego R.S. et al.EMAS position statement: the ten point guide to the integral management of menopausal health.Maturitas. 2015; 81: 88-92Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). It is generally recommended to continue EPT until age ∼50 years (the average age of natural menopause), unless a specific contraindication exists, such as an estrogen-dependent malignancy. In the present review, we discuss the use of HRT in women with POI and early menopause, including benefits and risks, HRT formulations available in the United States, management of HRT after age 50 in these women, and HRT use in special populations with POI. Women who experience ovarian insufficiency as a result of oophorectomy present a unique situation which will be addressed in a separate review. There are multiple etiologies for POI, including genetic, autoimmune, iatrogenic related to chemotherapy or radiation, surgical, and spontaneous presentation. Spontaneous 46,XX POI (sPOI) refers to ovarian insufficiency before the age of 40 years in women with a normal 46,XX karyotype for whom the condition develops spontaneously. In 90% of cases of sPOI, a specific underlying cause can not be identified. Approximately 4% of sPOI cases are due to lymphocytic autoimmune oophoritis caused by autoimmunity against steroidogenic cells, a process that may affect function of both the ovary and the adrenal glands (1Nelson L.M. Clinical practice. Primary ovarian insufficiency.N Engl J Med. 2009; 360: 606-614Crossref PubMed Google Scholar, 7Hoek A. Schoemaker J. Drexhage H.A. Premature ovarian failure and ovarian autoimmunity.Endocr Rev. 1997; 18: 107-134Crossref PubMed Scopus (282) Google Scholar). A premutation in the Fragile X Mental Retardataion 1 (FMR1) gene is responsible for an estimated 2%–5% of cases of isolated sPOI and 14% of familial sPOI cases (8Rafique S. Sterling E.W. Nelson L.M. A new approach to primary ovarian insufficiency.Obstet Gynecol Clin North Am. 2012; 39: 567-586Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 9Murray A. Schoemaker M.J. Bennett C.E. Ennis S. Macpherson J.N. Jones M. et al.Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.Genet Med. 2014; 16: 19-24Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The FMR1 gene contains a polymorphic trinucleotide (CGG) repeat, normally present in <45 copies, at the 5′ untranslated region. A full mutation of the FMR1 gene occurs when >200 CGG repeats exist and is the cause of fragile X syndrome, the most common heritable form of mental retardation. An FMR1 gene premutation, which may expand to the full mutation across generations, contains 55–199 CGG repeats, and incurs ∼24% risk of developing sPOI in carriers (9Murray A. Schoemaker M.J. Bennett C.E. Ennis S. Macpherson J.N. Jones M. et al.Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency.Genet Med. 2014; 16: 19-24Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The most common genetic cause of POI is Turner syndrome, which is most commonly related to a 45,X karyotype. Turner syndrome affects ∼1 in 2,500 girls (10Bondy C.A. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group.J Clin Endocrinol Metab. 2007; 92: 10-25Crossref PubMed Scopus (0) Google Scholar). Women with POI and early menopause commonly complain of bothersome menopausal symptoms, which may present gradually or suddenly. The symptoms these women experience are identical to those experienced by women who proceed through menopause naturally, and may include hot flashes, night sweats, insomnia, and sexual dysfunction due to vaginal dryness, dyspareunia, and loss of libido (11Graziottin A. Basson R. Sexual dysfunction in women with premature menopause.Menopause. 2004; 11: 766-777Crossref PubMed Google Scholar, 12Kalantaridou S.N. Vanderhoof V.H. Calis K.A. Corrigan E.C. Troendle J.F. Nelson L.M. Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency.Fertil Steril. 2008; 90: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13de Almeida D.M. Benetti-Pinto C.L. Makuch M.Y. Sexual function of women with premature ovarian failure.Menopause. 2011; 18: 262-266Crossref PubMed Scopus (0) Google Scholar, 14van der Stege J.G. Groen H. van Zadelhoff S.J. Lambalk C.B. Braat D.D. van Kasteren Y.M. et al.Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure.Menopause. 2008; 15: 23-31Crossref PubMed Scopus (0) Google Scholar). A decline in ovarian E2 production, and likely to some extent ovarian T production, is responsible for these symptoms (12Kalantaridou S.N. Vanderhoof V.H. Calis K.A. Corrigan E.C. Troendle J.F. Nelson L.M. Sexual function in young women with spontaneous 46,XX primary ovarian insufficiency.Fertil Steril. 2008; 90: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 14van der Stege J.G. Groen H. van Zadelhoff S.J. Lambalk C.B. Braat D.D. van Kasteren Y.M. et al.Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure.Menopause. 2008; 15: 23-31Crossref PubMed Scopus (0) Google Scholar, 15Kalantaridou S.N. Calis K.A. Vanderhoof V.H. Bakalov V.K. Corrigan E.C. Troendle J.F. et al.Testosterone deficiency in young women with 46,XX spontaneous premature ovarian failure.Fertil Steril. 2006; 86: 1475-1482Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Menopause symptoms should be taken seriously by affected women and their physicians, because these symptoms can affect quality of life and signal hormone deficiencies that may contribute to disease (16Thurston R.C. el Khoudary S.R. Sutton-Tyrrell K. Crandall C.J. Gold E. Sternfeld B. et al.Are vasomotor symptoms associated with alterations in hemostatic and inflammatory markers? Findings from the Study of Women’s Health Across the Nation.Menopause. 2011; 18: 1044-1051Crossref PubMed Scopus (0) Google Scholar). Appropriate physiologic estrogen replacement alleviates menopausal symptoms, and may improve sexual dysfunction that is related to vaginal dryness, dyspareunia, and decreased libido. A role for T replacement in treating menopausal symptoms, particularly those related to sexual dysfunction, has not been clearly established. There are currently no approved T formulations for women in the U.S. Furthermore, androgen deficiency in women is not well defined and therefore should not be diagnosed until normative data on T levels across a woman's lifespan have been established (17Wierman M.E. Basson R. Davis S.R. Khosla S. Miller K.K. Rosner W. et al.Androgen therapy in women: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2006; 91: 3697-3710Crossref PubMed Scopus (0) Google Scholar). That said, some reports have demonstrated that T replacement enhances the beneficial effects of estrogen therapy on sexual function in women with POI following oophorectomy (18Nachtigall L. Casson P. Lucas J. Schofield V. Melson C. Simon J.A. Safety and tolerability of testosterone patch therapy for up to 4 years in surgically menopausal women receiving oral or transdermal oestrogen.Gynecol Endocrinol. 2011; 27: 39-48Crossref PubMed Scopus (0) Google Scholar, 19Shifren J.L. Braunstein G.D. Simon J.A. Casson P.R. Buster J.E. Redmond G.P. et al.Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.N Engl J Med. 2000; 343: 682-688Crossref PubMed Scopus (0) Google Scholar, 20Braunstein G.D. Sundwall D.A. Katz M. Shifren J.L. Buster J.E. Simon J.A. et al.Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.Arch Intern Med. 2005; 165: 1582-1589Crossref PubMed Scopus (0) Google Scholar, 21Davis S.R. van der Mooren M.J. van Lunsen R.H. Lopes P. Ribot C. Rees M. et al.Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial.Menopause. 2006; 13: 387-396Crossref PubMed Scopus (0) Google Scholar, 22Floter A. Nathorst-Boos J. Carlstrom K. von Schoultz B. Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being.Climacteric. 2002; 5: 357-365Crossref PubMed Google Scholar). Multiple studies have shown that the lower bone mineral density (BMD) seen in women with POI or early menopause (age <45 years) due to any etiology is associated with significantly increased risk for fracture (23Gallagher J.C. Effect of early menopause on bone mineral density and fractures.Menopause. 2007; 14: 567-571Crossref PubMed Scopus (0) Google Scholar, 24Mallmin H. Ljunghall S. Persson I. Bergstrom R. Risk factors for fractures of the distal forearm: a population-based case-control study.Osteoporos Int. 1994; 4: 298-304Crossref PubMed Scopus (0) Google Scholar, 25Vega E.M. Egea M.A. Mautalen C.A. Influence of the menopausal age on the severity of osteoporosis in women with vertebral fractures.Maturitas. 1994; 19: 117-124Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 26Tuppurainen M. Kroger H. Honkanen R. Puntila E. Huopio J. Saarikoski S. et al.Risks of perimenopausal fractures—a prospective population-based study.Acta Obstet Gynecol Scand. 1995; 74: 624-628Crossref PubMed Google Scholar, 27Johansson C. Mellstrom D. An earlier fracture as a risk factor for new fracture and its association with smoking and menopausal age in women.Maturitas. 1996; 24: 97-106Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 28van Der Voort D.J. van Der Weijer P.H. Barentsen R. Early menopause: increased fracture risk at older age.Osteoporos Int. 2003; 14: 525-530Crossref PubMed Scopus (74) Google Scholar, 29van der Klift M. de Laet C.E. McCloskey E.V. Johnell O. Kanis J.A. Hofman A. et al.Risk factors for incident vertebral fractures in men and women: the Rotterdam Study.J Bone Miner Res. 2004; 19: 1172-1180Crossref PubMed Scopus (0) Google Scholar). Several of these studies further demonstrated that fracture rates are reduced among women with POI or early menopause who are treated with the use of HRT (23Gallagher J.C. Effect of early menopause on bone mineral density and fractures.Menopause. 2007; 14: 567-571Crossref PubMed Scopus (0) Google Scholar, 24Mallmin H. Ljunghall S. Persson I. Bergstrom R. Risk factors for fractures of the distal forearm: a population-based case-control study.Osteoporos Int. 1994; 4: 298-304Crossref PubMed Scopus (0) Google Scholar, 26Tuppurainen M. Kroger H. Honkanen R. Puntila E. Huopio J. Saarikoski S. et al.Risks of perimenopausal fractures—a prospective population-based study.Acta Obstet Gynecol Scand. 1995; 74: 624-628Crossref PubMed Google Scholar, 29van der Klift M. de Laet C.E. McCloskey E.V. Johnell O. Kanis J.A. Hofman A. et al.Risk factors for incident vertebral fractures in men and women: the Rotterdam Study.J Bone Miner Res. 2004; 19: 1172-1180Crossref PubMed Scopus (0) Google Scholar). Peak bone mass is attained by the age of ∼30 years in women; prolonged estrogen deficiency before this age results in decreased peak bone mass accrual, and estrogen deficiency after this age results in early bone loss. Early BMD loss or failure to attain peak bone mass results in increased fracture risk and is a primary health concern among young women with POI, particularly if appropriate treatment with the use of HRT is not initiated soon after disease onset (1Nelson L.M. Clinical practice. Primary ovarian insufficiency.N Engl J Med. 2009; 360: 606-614Crossref PubMed Google Scholar, 30Anasti J.N. Kalantaridou S.N. Kimzey L.M. Defensor R.A. Nelson L.M. Bone loss in young women with karyotypically normal spontaneous premature ovarian failure.Obstet Gynecol. 1998; 91: 12-15Crossref PubMed Scopus (0) Google Scholar, 31Ohta H. Sugimoto I. Masuda A. Komukai S. Suda Y. Makita K. et al.Decreased bone mineral density associated with early menopause progresses for at least ten years: cross-sectional comparisons between early and normal menopausal women.Bone. 1996; 18: 227-231Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 32Leite-Silva P. Bedone A. Pinto-Neto A.M. Costa J.V. Costa-Paiva L. Factors associated with bone density in young women with karyotypically normal spontaneous premature ovarian failure.Arch Gynecol Obstet. 2009; 280: 177-181Crossref PubMed Scopus (0) Google Scholar, 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar). Compared with regularly menstruating similarly aged women, a cohort of young women with 46,XX sPOI (mean age 32 years, range 20–39) had significantly lower BMD z-scores. Importantly, 21% of women with sPOI in this cohort had BMD z-scores less than −2.0, indicative of low BMD for age and a fracture risk factor (33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar). Fully 67% of these women with sPOI had femoral neck BMD z-scores less than −1.0, and among women with sPOI who were within 1.5 years of diagnosis, almost one-half (47%) had femoral neck z-scores less than −1.0. Progressive decreases in ovarian hormone production occurring well before the diagnosis of sPOI may perhaps contribute to the high rates of low BMD in women who were recently diagnosed. It is important to address modifiable risk factors that may contribute to reduced bone mass (Table 1) (33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar). Delay in diagnosis is a contributing risk factor for women with POI. In one study of POI, more than 50% of women had to visit three or more different clinicians with a complaint of menstrual abnormality before an FSH level was measured (34Alzubaidi N.H. Chapin H.L. Vanderhoof V.H. Calis K.A. Nelson L.M. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure.Obstet Gynecol. 2002; 99: 720-725Crossref PubMed Scopus (0) Google Scholar). It is important to view the menstrual cycle as a vital sign of bone health and to investigate abnormalities aggressively. To support bone health, women with POI need to assure adequate calcium and vitamin D intake and maintain a routine of regular weight-bearing exercise. In a group of women with POI, Popat et al. found that 58% had inadequate serum 25-hydroxy vitamin D levels, 49% had inadequate calcium intake, and almost one out of four had no regular exercise program (33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar). Clinicians should maintain serum 25-hydroxy vitamin D levels in the normal range (>30 ng/mL) (35Holick M.F. Binkley N.C. Bischoff-Ferrari H.A. Gordon C.M. Hanley D.A. Heaney R.P. et al.Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2011; 96: 1911-1930Crossref PubMed Scopus (2217) Google Scholar). Women with POI should take 1,000–2,000 IU vitamin D3 (cholecalciferol) daily, along with 1200 mg of elemental calcium, either through dietary sources or supplements to optimize bone health (1Nelson L.M. Clinical practice. Primary ovarian insufficiency.N Engl J Med. 2009; 360: 606-614Crossref PubMed Google Scholar). Additional risk factors for low BMD in women with POI include older age, younger age at POI diagnosis (particularly diagnosis before the age of peak bone mass accrual), and lower body mass index (32Leite-Silva P. Bedone A. Pinto-Neto A.M. Costa J.V. Costa-Paiva L. Factors associated with bone density in young women with karyotypically normal spontaneous premature ovarian failure.Arch Gynecol Obstet. 2009; 280: 177-181Crossref PubMed Scopus (0) Google Scholar). Interestingly, race other than white was a risk factor for reduced BMD in Black, Asian, and Hispanic women with POI (Table 2) (33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar). These differences disappeared when corrected for other factors, a distressing fact pointing out problems with racially biased health disparities (Table 3) (33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar). Altogether, women with POI need physiologic HRT and healthy lifestyle habits to maintain bone density and minimize fracture risk.Table 1Risk factors for z-score less than −2 at any site as assessed by means of prevalence proportional ratio (PPR) in women with primary ovarian insufficiency (n = 442).Risk factorPPR95% CIP valueOnset of menstrual irregularity before age 20 y2.721.74–4.33<.0001Delay in diagnosis >1 y1.961.14–3.35.018Serum 25(OH) vitamin D <32 ng/mL2.891.47–5.69.002No regular exercise1.931.22–3.06.005Weight <55 kg2.81.47–5.36.002Daily calcium intake <1,000 mg2.81.37–5.75.005Smoking >2 cigarettes/day0.910.25–3.39.84Note: Adapted with permission from Popat et al. 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar. CI = confidence interval. Open table in a new tab Table 2Risk for serum 25(OH) vitamin D deficiency (<32 ng/mL) and bone mineral density z-score less than −2 according to race/ethnicity in women with primary ovarian insufficiency (n = 442).Race/ethnicityPPR95% CIP valueWhite1.940.88–4.28.099African-American6.743.17–14.3<.0001Asian9.074.1–20.04<.0001Hispanic3.881.35–11.2.012Note: Adapted with permission from Popat et al. 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar. Abbreviations as in Table 1. Open table in a new tab Table 3Serum 25(OH) vitamin D levels, calcium intake, and compliance to hormone replacement therapy (HRT) according to race/ethnicity Serum 25(OH)-Vit D (ng/mL) Calcium Intake (mg/day) HRT Compliance.Race/ethnicitySerum 25(OH) vitamin D, ng/mL (n = 429)Calcium intake (n = 250)HRT compliance (n = 423)nMean (SEM)P valuenMean (SEM)P valuenCompliant (%)P valueWhite33733.6 (0.8)–2051,947 (49)–33675–African-American4819.3 (2.3)<.001251,716 (144)<.0014466.20Asian1817.1 (3.7)<.00171,258 (142).0161844.01Hispanic2624.8 (3).01131,803 (241)<.0012564.24Note: Adapted with permission from Popat et al. 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar. Open table in a new tab Note: Adapted with permission from Popat et al. 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar. CI = confidence interval. Note: Adapted with permission from Popat et al. 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar. Abbreviations as in Table 1. Note: Adapted with permission from Popat et al. 33Popat V.B. Calis K.A. Vanderhoof V.H. Cizza G. Reynolds J.C. Sebring N. et al.Bone mineral density in estrogen-deficient young women.J Clin Endocrinol Metab. 2009; 94: 2277-2283Crossref PubMed Scopus (0) Google Scholar. The National Institutes of Health (NIH) Intramural Research Program conducted a 3-year prospective randomized controlled trial in young women with 46,XX sPOI to investigate the effectiveness of a standardized regimen of HRT on BMD. The study used treatment with the use of physiologic E2 replacement with cyclic oral progestin (100 μg/d transdermal E2 with 10 mg oral medroxyprogesterone daily for 12 days per month). This replacement therapy improved lumbar spine and femoral neck BMD, such that at the end of the 3-year intervention, BMD did not differ between women with sPOI and a group of contemporaneously recruited normally cycling control women (Fig. 1) (36Popat V.B. Calis K.A. Kalantaridou S.N. Vanderhoof V.H. Koziol D. Troendle J.F. et al.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.J Clin Endocrinol Metab. 2014; 99: 3418-3426Crossref PubMed Scopus (0) Google Scholar). The addition of transdermal T replacement to the regimen of transdermal E2 and oral medroxyprogesterone acetate provided no additional beneficial effect on BMD (36Popat V.B. Calis K.A. Kalantaridou S.N. Vanderhoof V.H. Koziol D. Troendle J.F. et al.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.J Clin Endocrinol Metab. 2014; 99: 3418-3426Crossref PubMed Scopus (0) Google Scholar). Important evidence is accumulating to support a conclusion that physiologic HRT (transdermal E2 and cyclic progestin) is more effective in maintaining bone health in young women with POI than continuous combined therapy with oral contraceptive pills (OCPs). For example, a study in women with POI comparing the efficacy of 12 months of physiologic HRT (100–150 μg/d transdermal E2 plus cyclic progestin) with 12 months of a combined OCP (30 μg ethinyl E2 and 1.5 mg norethisterone daily for 3 weeks per month) demonstrated that physiologic HRT was superior to OCPs in protecting and improving BMD (37Crofton P.M. Evans N. Bath L.E. Warner P. Whitehead T.J. Critchley H.O. et al.Physiological versus standard sex steroid replacement in young women with premature ovarian failure: effects on bone mass acquisition and turnover.Clin Endocrinol (Oxf). 2010; 73: 707-714Crossref PubMed Scopus (0) Google Scholar). Another 2-year open-label randomized trial in women with POI compared physiologic E2 replacement (2 mg oral E2 and 0.075 mg levonorgestrel daily) with combined OCP (0.030 mg ethinyl E2 and 0.150 mg levonorgestre" @default.
• W2559178581 created "2016-12-08" @default.
• W2559178581 creator A5025677244 @default.
• W2559178581 creator A5043936869 @default.
• W2559178581 creator A5049551167 @default.
• W2559178581 date "2016-12-01" @default.
• W2559178581 modified "2023-10-10" @default.
• W2559178581 title "Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause" @default.
• W2559178581 cites W106605389 @default.
• W2559178581 cites W137975887 @default.
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