Follicle-Stimulating Hormone in Mothers of Twins
Follicle-Stimulating Hormone in Mothers of Twins
ABSTRACT & COMMENTARY
Synopsis: Premenopausal women who have given birth to dizygotic twins have higher FSH levels on day 3 of the menstrual cycle.
Source: Lambalk CB, et al. J Clin Endocrinol Metab 1998;83:481-486.
Every patient who has been told she is having twins wants to know what causes this event. So, every obstetrician must have been asked this question at least once. Lambalk and colleagues sought the answer by studying 16 premenopausal women and nine postmenopausal women who had given birth to dizygotic twins. There were 14 premenopausal and eight postmenopausal control women. Blood samples were obtained at 10-minute intervals for six hours on day 3 of the cycle in the premenopausal women and on a random day in the postmenopausal women. This was followed by a 100 mcg GnRH stimulation test. The apparent reason for hereditary dizygotic twinning is, not surprisingly, more FSH. Lambalk et al went to great lengths to show that LH levels, LH pulse frequency, and inhibin A and inhibin B levels do not differ between premenopausal twin mothers and premenopausal singleton mothers. This was interpreted by Lambalk et al as evidence against an ovarian cause of increased FSH. There were no discernible hormonal or demographic differences between postmenopausal twin and singleton mothers. The age of menopause did not differ. Lambalk et al conclude that increased GnRH drive is not the cause of twinning, but the cause of the increased FSH remains mysterious.
COMMENT BY SARAH L. BERGA, MD
At first blush, this study might seem pointless because the answer seems self-evident. However, there is some fascinating physiology contained in this well-designed and executed study. Like most good studies, it raises more questions than it answers. This question first intrigued me when I had a colleague whose mother had four sets of dizygotic twins and no singleton pregnancies. Thinking of herself, of course, my colleague wanted to know if these things could be detected so as to permit a singleton gestation rather than a twin gestation.
First, let's consider how more FSH might lead to dizygotic twinning on day 3 of the follicular phase. Generally, FSH recruits responsive follicles that grow until one secretes enough estradiol to suppress FSH below the threshold needed for further follicular growth. The dominant follicle escapes demise by becoming FSH-independent and LH-dependent. Iatrogenic multifollicular growth occurs when the fall in FSH is prevented. But, that, presumably, is not what occurs in hereditary dizygotic twinning. There must be two follicles of equal maturity by the time FSH falls. Do higher FSH levels on day 3 of the menstrual cycle permit greater follicle synchrony, or do twin mothers have more follicles on day 3? The age of menopause did not differ in this study, although in one other study, the age of menopause was earlier. If the age of menopause does not differ, then there is either greater synchrony or a greater cohort of follicles at any given time. A greater cohort would likely be revealed as higher inhibin levels, and these were not found. Thus, the most likely explanation is that higher FSH levels on day 3 of the follicular phase allow greater follicular synchrony.
Second, let's consider what might make FSH levels higher. Greater GnRH drive might, but that would also lead to higher LH levels, which were not found. Increased GnRH pulse frequency is an unlikely cause, because available evidence suggests that higher frequencies depress FSH and increase LH, leading to polycystic ovary syndrome (Daniels TL, Berga SL. J Clin Endocrinol Metab 1997;82:4179-4183.) Further, in both the premenopausal and postmenopausal twin mothers, LH pulse frequency did not differ from control women. Also, FSH release in response to GnRH was not greater and not exclusively synchronized with LH pulses. Inhibin levels were neither lower nor higher. Taken together, these data suggest that an unidentified factor amplifies FSH in hereditary dizygotic twinning.
Third, the present study forces us to consider our interpretation of an elevated day 3 FSH. As this study reveals, a mildly elevated day 3 FSH does not invariably indicate incipient ovarian failure. Fortunately, it is likely to be more predictive of ovarian reserve when used exclusively in an infertile population.
The next time a patient asks you what causes dizygotic twinning, you can confidently answer increased FSH-and hope that she doesn't ask what causes the increased FSH.
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