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Evidence of Early Ovarian Aging in Fragile X Premutation Carriers

Reproductive Endocrine Unit (C.K.W., P.C.S.), Department of Medicine, Massachusetts General Hospital, Boston Massachusetts 02114; and Pfizer Global Research and Development (A.E.T.), Groton Laboratories, Groton, Connecticut 06340

Address all correspondence and requests for reprints to: Corrine Welt, Reproductive Endocrine, BHX 511, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: cwelt{at}partners.org.

Up to 28% of female fragile X premutation carriers develop premature ovarian failure. To test the hypothesis that fragile X premutation carriers with ovulatory menstrual cycles exhibit hormone changes characteristic of early ovarian aging, 11 regularly cycling fragile X premutation carriers, 24–41 yr old (34.5 ± 5.7 yr, mean ± SD), drew daily blood samples across one menstrual cycle. LH, FSH, estradiol, progesterone (P4), inhibin A, and inhibin B levels were compared with levels in 22 age-matched, regularly cycling women, 23–41 yr old (34.6 ± 5.8 yr), at each cycle stage.

Total cycle (26.1 ± 1.0 vs. 28.2 ± 0.4 d; P < 0.05) and follicular phase length (12.9 ± 0.8 vs. 14.5 ± 0.4 d; P < 0.05) were decreased in fragile X premutation carriers compared with age-matched controls, whereas luteal phase length was similar (13.2 ± 0.5 vs. 13.7 ± 0.3 d; P = not significant). FSH was elevated across the follicular (21.9 ± 3.5 vs. 11.2 ± 0.5 IU/liter; P < 0.001) and luteal phases (14.6 ± 3.9 vs. 7.9 ± 0.5 IU/liter; P < 0.05) in fragile X premutation carriers compared with age-matched controls. Inhibin B in the follicular phase (77 ± 11 vs. 104 ± 6 pg/ml; P < 0.05) and inhibin A (3.4 ± 0.7 vs. 5.8 ± 0.5 IU/ml; P < 0.01) and P4 [7.3 ± 1.0 vs. 10.1 ± 0.7 ng/ml (23.2 ± 3.0 vs. 32.1 ± 2.3 nmol/liter); P < 0.05] in the luteal phase were decreased in fragile X premutation carriers compared with age-matched controls, whereas there was no difference in estradiol or LH.

In summary, despite regular ovulatory cycles, FSH was increased in fragile X premutation carriers compared with age-matched controls. The increased FSH was accompanied by decreased inhibin B in the follicular phase and inhibin A and P4 in the luteal phase. These hormonal changes suggest that fragile X premutation carriers exhibit early ovarian aging despite regular menstrual cycles. Early ovarian aging in fragile X premutation carriers likely results from decreased follicle number and function, as reflected by lower inhibin B, inhibin A, and P4 levels.

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