Arch Gynecol Obstet (2005) 273: 17–19 DOI 10.1007/s00404-005-0029-7 O R I GI N A L A R T IC L E Dilek Uygur Æ Özlem Sengül Æ Didem Bayar Seval Erdinç Æ Sertaç Batıoğlu Æ Leyla Mollamahmutoglu Bone loss in young women with premature ovarian failure Received: 8 August 2004 / Accepted: 25 March 2005 / Published online: 11 July 2005
Springer-Verlag 2005 Abstract Objective: To evaluate the effect of premature ovarian failure on bone mineral density. Materials and methods: Forty-five women with karyotypically normal spontaneous premature ovarian failure underwent hip and spinal bone density measurements by dual energy Xray absorptiometry. Findings were compared with a control group of 61 women of similar age. Results: The median (range) age of the women with premature ovarian failure was 33 (18–39) years. The median (range) time since diagnosis of premature ovarian failure was 2 years (0.5–7). Forty-one of the women (91%) had sought medical advice previously and had taken a variety of estrogen and progestin replacement regimens at least intermittently. Both the femoral neck bone mineral density measurements and the spinal bone mineral density measurements were significantly lower than measurements of the control group (P<0.05). Conclusion: Our study shows that premature ovarian failure has significantly lower levels of bone mineral density than the control group of normal women. We suggest that hormone replacement therapy should be substituted early and consistently in affected patients. Our data also raise questions about whether preservation of bone mass in these patients will require replacement of additional gonadal steroids. Keywords Premature ovarian failure Æ Hormone replacement therapy Æ Osteoporosis D. Uygur (&) Æ Ö. Sengül Æ D. Bayar Æ S. Erdinç S. Batıoğlu Æ L. Mollamahmutoglu Zekai Tahir Burak Women Health Care, Research and Education Hospital, 33. Cadde, 16/27, Isci Bloklari Mahallesi, Karakusunlar, Cankaya, Ankara, 06520, Turkey E-mail: uygurdc@superonline.com Fax: +90-312-4260004 Introduction Women with normal ovarian function achieve peak femoral bone mineral density in their early 1920s [1]. Sex steroids play an important role in maintaining bone mass, and cessation of ovarian function results in significant bone loss [2]. By age 40, one percent of women spontaneously develop premature ovarian failure (POF); a condition that causes amenorrhoea, elevated gonadotropins, hypoestrogenemia, and hypoandrogenemia [3, 4]. Premature ovarian failure is one of the major risk factors associated with the development of osteoporosis [5]. Ideally, hormone replacement strategies for young women with premature ovarian failure should maintain bone mass as well as the normal ovary maintains bone mass in regularly menstruating women. The aim of the current study was to assess the effect of spontaneous premature ovarian failure on bone mineral density. Materials and methods We recruited 45 women with premature ovarian failure who were admitted to our infertility clinic between 2002 and 2003. We used the following criteria for diagnosing POF: ‡4 months of amenorrhoea and two serum values of >40 mIU/ml obtained ‡1 month apart in a woman <40 years of age. Women with iatrogenic causes of premature ovarian failure or chromosomal abnormalities were excluded from the study. Bone mineral density of the hip and spine were measured by dual energy X-ray absorptiometry. Sixty-one young women with normal menstrual cycles and normal levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) served as the control group for bone density measurements. All the women in 18 the control group were free of any chronic diseases (including renal disease, amenorrhoea, hyperthyroidism, and hyperparathyroidism) or medications (including corticosteroids and chronic anticonvulsant use) known to affect bone metabolism. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. The Statistical Program for Social Sciences (SPSS) for Windows software was used for the calculations. The statistical analysis was performed using Student’s t test and P<0.05 was considered significant. Results The median age of the patients with premature ovarian failure was 33 (18–39) years and of the women in the control group 35 (20–39) years. The median (range) time since diagnosis of premature ovarian failure was 2 (0.5– 7) years. The mean [± standard deviation (SD)] (BMI) of the patients was 24.3±4.5 kg/m2 and of the control group was 23.5±4.2 kg/m2. Forty-one of the patients (91%) had sought medical advice previously regarding amenorrhoea or infertility and had received a variety of regimens of estrogen and progestin replacement therapies at least intermittently. Since the women were not asked specifically about the current side effects or the reason for discontinuation of the hormone replacement therapy, only the ones who report their concerns about current or long-term side effects were recorded. Only 5 (11.1%) women have reported their fears about the breast cancer related to the therapy. None of the women have complained about the current side effects of the hormone replacement therapy. Thirty-six of the patients (80%) were receiving calcium supplementation. Measurements of femoral neck bone mineral density and spinal (L1–4) bone mineral density were demonstrated in Table 1. None of the women had any bone fracture. Both the femoral neck bone mineral density measurements and the spinal bone mineral (L1– L4) density measurements were significantly lower than measurements of the control group (P<0.05). Discussion Premature menopause is a distressing event of enormous consequence for the women in whom it occurs. In contrast to ovarian failure that develops abruptly as a result of surgical castration, chemotherapy, or radiation, estrogen deficiency may occur insidiously in women with Table 1 Bone mineral density measurements of the women BMD (mean±SD) POF (n=45) Healthy women (n=61) Statistical significance Femur neck L1–L4 0.715±0.23 0.913±0.34 0.762±0.28 0.985±0.21 P<0.05 P<0.05 karyotypically normal spontaneous premature ovarian failure. Indeed, menstrual irregularities occur often in the years preceding premature ovarian failure, and menstrual irregularities have been associated with significant bone loss [6]. Hormone replacement for these young women, some of whom develop ovarian failure even before they reach peak adult bone mass, should ideally mimic normal ovarian function as closely as possible. Current hormone replacement strategies were developed for women who experience natural menopause at an average age of 50. The postmenopausal estrogen–progestin interventions trial showed that estrogen–progestin replacement therapy could maintain bone mass in postmenopausal women 45–64 years of age. However, these strategies may be inadequate for young women with premature ovarian failure. Indeed, the recognized bone-sparing dose of 0.625 mgr of conjugated estrogen failed to prevent vertebral bone loss in premenopausal women made estrogen-deficient by gonadotropin-releasing hormone agonist therapy [7]. The normal premenopausal ovary produces estrogen, progesterone, and androgen. A prospective study has shown that low serum androgen levels are associated with greater bone loss in all women (premenopausal, perimenopausal, and postmenopausal). Furthermore, in postmenopausal women, androgen replacement along with estrogen has been shown to increase spinal bone mineral density significantly more than estrogen alone [8]. Women with premature ovarian failure have lower androgen levels than normal ovulatory women. This raises the possibility that androgen replacement along with estrogen may be necessary to maintain bone mass in these young women. Young women with karyotypically normal spontaneous premature ovarian failure face decades of exposure to hormone replacement therapy. Although our patients had previously sought medical advice and most of them had taken estrogen and progestin replacement therapy at least intermittently, they had reduced bone mineral density compared with similar-age women with normal ovarian function. The reason why we did not see any women with a history of bone fractures might be related to the short median interval since diagnosis of the POF of women in our series. It is clear that these young women need ongoing medical evaluation and education regarding the need for hormone replacement, physical activity, and adequate calcium intake. Furthermore, strategies to improve compliance are needed. Fear of breast cancer is frequently a reason for compliance failure. The concerns regarding estrogen therapy in postmenopausal women may not be directly related to young women with premature ovarian failure [4]. Postmenopausal women are prolonging their exposure to estrogen effect beyond the normal age range. In contrast, women with premature ovarian failure take estrogen to replace what their ovary should be making normally. In conclusion, our study shows that women with karyotypically normal spontaneous premature ovarian 19 failure have significantly lower levels of bone mineral density than the control group of normal women. We suggest that hormone replacement therapy should be substituted early and consistently in affected patients. These young women need early education regarding strategies to maintain their bone mass and ongoing medical evaluation to maintain compliance with these strategies. Our data also raise questions about whether preservation of bone mass in these patients will require replacement of additional gonadal steroids. References 1. Rodin A, Murphy B, Smith MA, Caleffi M, Fentiman I, Chapman MG et al (1990) Premenopausal bone loss in the lumbar spine and neck of femur: a study of 225 caucasian women. Bone 11:1–5 View publication stats 2. Rizzoli R, Bonyour JP (1997) Hormones and bones. Lancet 349(Suppl)1:20–23 3. Caulam CB, Adamson SC, Annegers JF (1996) Incidence of premature ovarian failure. Obstet Gynecol 67:604–606 4. Nelson LM, Anasti JN, Flack MR (1996) Premature ovarian failure. In: Adashi EY, Rock JA, Rozenwaks Z (eds) Reproductive endocrinology, surgery, and technology. LippincottRaven, Philadelphia, pp 1394–410 5. Alpler MM, Garner PR (1985) Premature ovarian failure: its relationship to autoimmune disease. Obstet Gynecol 66:27–30 6. Prior JC, Vigna YM, Schechter MT, Burgess AE (1990) Spinal bone loss and ovulatory disturbances. N Eng J Med 323:1221– 1227 7. Sugimoto AK, Hodsman AB, Nisker JA (1993) Long-term gonadotropin releasing hormone agonist with standard postmenopausal estrogen replacement failed prevent vertebral bone loss in premenopausal women. Fertil Steril 60:672–674 8. Watts NB, Notelovitz M, Timmons MC, Addison WA, Wiita B, Downey LJ (1995) Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol 85:529–537