Table 1.
Characteristics of Included Studies
| Study and F/U | Inclusion/Exclusion Criteria, Demographics, and Risk Factors | Interventions (No. of Patients) |
|---|---|---|
| Castelo-Branco, 2001 [20] | Inclusion criteria: amenorrhea (no menstruation for 6 mo) or oligomenorrhea (6 or fewer menstrual periods during the previous year). Depressed and anxiety prone. Exclusion: AN, current use of any drug that may affect bone mass, renal or GI disease, thyroid dysfunction, DM, moderate to severe osteopenia (T score ≤1.5) or osteoporosis (T score ≤2.5) | OCP (0.03 EE + desogestrel) [24] |
| Length of F/U: 12 mo | Demographics: age, 24.4 y ± 7.9; race, NR; BMI, 23.7 kg/cm2; length of amenorrhea, 16.7 ± 10.4 mo | EE 0.030 mg and desogestrel 0.15 mg |
| Risk factor: stress (patients were depressed and anxiety prone) | OCP (0.02 EE + desogestrel) [22] | |
| EE 0.020 mg and desogestrel 0.15 mg | ||
| Control [18] | ||
| No treatment | ||
| Cumming, 1996 [25] | Inclusion criteria: Confirmation of the pathophysiology of the amenorrhea and bone density measurement by DXA if amenorrheic for longer than 2 y. Bone density >1.0 SD below the mean value. Characteristic picture of exercise-associated amenorrhea (low/low-normal LH, FSH, estradiol, and prolactin) | HRT (CE/estradiol + MPA) [8] |
| Length of F/U: 24-30 months | Demographics: age, 23-34 y; race, NR; BMI, 17.1 kg/cm2; length of amenorrhea, 2-8 y | Conjugated estrogen 0.625 mg (n = 6), or estradiol transdermal patch 50 μg daily with cyclic medroxyprogesterone acetate 10 mg daily for 14 d monthly (n = 2) for at least 2 y |
| Risk factor: exercise (run 35-75 miles/wk) | Control [5] | |
| No treatment | ||
| De Cree, 1998 [23] | Inclusion criteria: Sportswomen aged 18-29 y. Athletic amenorrhea with osteoporosis. Free for at least 3 months of any medical drugs known to interfere with calcium or sex hormone metabolism. Amenorrhea (no menstruation for at least 6 mo) or oligomenorrhea (decreased frequency of menstrual cycles in the previous year with only 1 menstrual period during last 3 mo) | OCP (EE + CPA) [7] |
| Length of F/U: 8 mo | Demographics: age, 21.9 ± 3.9 y; race, NR; BMI, NR; length of amenorrhea, NR (as defined previously) | EE 0.05 mg and cyproterone acetate 2 mg |
| Risk factor: exercise (run 21.7 ± 9.3 miles/wk). Stress (27% had stressful life) | Control [4] | |
| No treatment | ||
| Gibson, 1999 [21] | Inclusion criteria: subjects had to have trained for 3 y and currently training for a minimum of 3 h/wk and to run at least 40 km/wk. Exclusion: history of respiratory disease, DM, metabolic bone disorders, rheumatoid arthritis, thyroid or parathyroid disease, malignancy, cardiac, renal or inflammatory bowel disease. Patients taking oral or inhaled steroids | Hormone replacement (estriol, estradiol, and norethisterone) + calcium supplements [10] |
| Length of F/U: 9 mo (18 mo, but outcomes were reported for 9 mo of F/U) | Demographics: age, 27.5 ± 9.3 y; race, 100% white; BMI, 19.21 kg/cm2; length of amenorrhea, 6.9 y | Daily oral treatment with Trisequens tablets (estriol 1 mg and estradiol 2 mg for 12 d; estriol 1 mg, estradiol 2 mg, and norethisterone acetate 1 mg for 10 d; estriol 0.5 mg and estradiol 1 mg for 6 d) + 1000 mg calcium carbonate |
| Risk factor: exercise (run 53.1 ± 13.8 miles/wk) | Calcium supplements [14] | |
| 1000 mg calcium carbonate per day | ||
| Control [10] | ||
| No treatment | ||
| Hergenroeder, 1997 [24] | Inclusion criteria: hypothalamic amenorrhea (no menstrual bleeding in the past 6 mo) and oligomenorrhea (6 or fewer menstrual periods in the past 12 mo, with 1 or more menstrual periods in the past 6 mo) associated with a lifestyle that included exercise, weight loss, dieting, or stress. Exclusion: evidence of disease that would affect bone mineral, the use of medications that affect bone mineral, tobacco use, and obesity (>120% of estimated ideal weight) | OCP (EE + norethindrone) [5] |
| Demographics: age, 20.1 ± 7.4 y; race, 100% white; BMI, 18 kg/cm2; length of amenorrhea, NR (as defined previously) | EE 0.035 mg and norethindrone 0.5-1.0 mg/d on 21 d of each 28-d cycle | |
| Risk factor: exercise (80% of patients exercised as a part of a team or independently), dieting, stress | Medroxyprogesterone [5] | |
| Medroxyprogesterone 10 mg/d on the last 12 d of the calendar month | ||
| Placebo [5] | ||
| One placebo tablet daily for the last 12 d of the calendar month | ||
| Warren, 2003 [22] | Inclusion criteria: elite ballet dancers solicited from national and regional schools and dance companies, via advertisements in college publications, and by physician referrals for hormonal problems and interest in bone density measurements. Amenorrheics (no menstruation for at least 5 mo). Exclusion: patients taking hormones or oral contraceptives for 6 mo before the study | Hormone replacement (CE + MPA) [13] |
| Length of F/U: 24 months | Demographics: age 20.1 ± 4.6 y; race, 100% white; BMI, 18.87 kg/cm2; length of amenorrhea, NR (as defined previously) | CE 0.635 mg on d 1-25 + medroxyprogesterone 10 mg on d 16-25, in a 30-d circle + calcium supplements |
| Risk factor: exercise (dancing 24.0 ± 10.8 h/w) | Control [11] | |
| Placebo + calcium supplements | ||
| Rickenlund, 2004 [26] | Inclusion criteria: female athletes in endurance sports. 16-35 y, BMI 18-24, nulliparous, healthy, nonsmoking. Endurance training defined as a minimum of 6 h of aerobic weight-bearing training or a minimum of 70 km of running or 6 h of specific endurance training weekly. Amenorrhea (no menstruation for at least 3 mo) or oligomenorrhea (menstrual periods at intervals exceeding 6 wk) | OCP (EE + levonorgestrel) [13] |
| Length of F/U: 10 months | Demographics: age, 19.8 ± 4.6 y; race, NR; BMI, 19.4 kg/cm2; length of amenorrhea, NR (as defined previously) | EE 0.03 mg + levonorgestrel 0.15 mg on d 1-21, followed by a hormone- and tablet-free interval on d 22-28 |
| Risk factor: exercise (train 8.1 ± 1.6 h/wk) | ||
| Sowińska-Przepiera, 2011/2011 [27, 28] | Inclusion criteria: girls 16-17 y with FHA. (1) At least 6 mo of amenorrhea preceded by at least 3 y of oligomenorrhea; (2) psychological problems (learning disabilities and/or family problems). Exclusion: PCOS, CAH, premature ovarian failure, low birth weight or preterm birth, confirmed episode of an eating disorder, poor dieting during childhood or puberty, episodes of impaired growth and body mass gain, extensive participation in sports, metabolic disorders associated with decreased bone mineralization, prolonged use of stimulants or drugs that may affect bone metabolism, familial history of osteoporosis, incomplete 4-y F/U | OCP (17B-estradiol + dydrogesterone) |
| Length of F/U: 24 mo | Demographics: age, 16.7 ± 1.2 y; race, NR; BMI, 18.7 ± 2.2 kg/cm2; length of amenorrhea NR (as defined previously) | 17-b estradiol (2 mg from the second to 25th day of the menstrual cycle) and dydrogesterone (10 mg from the 16th to the 25th day of the menstrual cycle) |
| Risk factor: stress (psychological problems, defined previously) | ||
| Warren, 2005 [29] | Inclusion criteria: age, 18-40 y, with lumbar spine BMD ≥0.937 g/cm2 (DXA scan) and BMI 16-24 kg/m2. No menstrual periods during the last 3 months and 2 or fewer periods during the previous 12 mo or women with previously diagnosed FHA with no spontaneous menses during the previous 3 mo. Less than 6 months of hormonal therapy in the previous year. Women age 35-40 y required to be nonsmokers and those ages 18-34 y could not smoke more than 10 cigarettes per day. Exclusion: Pregnant, nursing, a contraindication for steroid hormonal therapy, evidence of cervical dysplasia, undiagnosed breast lesion, medical condition that could contribute to osteopenia, history of severe migraines, hypertension, hormonal therapy within 3-6 mo of screening, high prolactin, FSH, testosterone, LH/FSH ratio or LH >11, hirsutism, AN within 12 mo, or recent history of alcohol or other substance abuse. Medications that may interact with OCPs | OCP (EE + NGM) [27] |
| Length of F/U: 9 months | Demographics: age, 26.7 ± 6.64 y; race, 92.6% white and 7.4% other; BMI, 20.54 kg/cm2; length of amenorrhea 18.5 mo | EE 0.035 mg and norgestimate 0.180-0.250 mg on 21 d of each 28-d cycle. 10-13 cycles |
| Risk factor: NR |
Abbreviations: BMI, bone mass index; CAH, congenital adrenal hypoplasia; CE, conjugated estrogen; CPA, cyproterone acetate; DM, diabetes mellitus; DXA, dual energy x-ray absorptiometry; EE, ethinyl estradiol; FSH, follicle-stimulating hormone; F/U, follow-up; HRT, hormone replacement therapy; GI, gastrointestinal; LH, luteinizing hormone; MPA, medroxyprogesterone acetate; NR, not reported; PCOS, polycystic ovarian syndrome; SD, standard deviation.