European Journal of Obstetrics & Gynecology and Reproductive Biology
Hypothetical risks of twinning in the natural menstrual cycle
Introduction
Dizygotic (DZ) twinning is likely the result of multiple ovulation upon multiple ongoing follicle growth 1, 2. Well-known conditions with an increased incidence of DZ twinning are a hereditary trait, high maternal age and ovulation induction treatments 3, 4. The tremendous increase in twinning over the past two decades is mainly due to artificial reproductive techniques (Fig. 1). Under all these conditions a high exposure of the ovary to gonadotropic hormones is an associated phenomenon. Several studies have demonstrated elevated FSH levels at time of recruitment (perimenstrual period) of new ovarian follicles in mothers that had familial DZ twins 5, 6, 7. An increase of FSH levels around recruitment is a clear feature of ageing of the premenopausal female (Fig. 2) 8, 9, 10, 11, 12. The role of (over)stimulation with gonadotropic hormones in ovulation induction programs is obvious. From the above, it follows that Milham's old hypothesis of the contribution of elevated levels of FSH as the cause of DZ twinning is valid [13].
In normal women, monofollicular growth only takes place when a certain threshold in the level of plasma FSH is only marginally exceeded [14]. Multiple follicle growth is related to FSH levels being considerably higher than the earlier mentioned threshold [15]or to levels exceeding the threshold for too long a time [16]. Thus, FSH levels and the duration of this elevation are important determinants in final numbers of follicles that continue to grow until ovulation. In the human this has to be maintained at such levels that preferably one follicle continues to grow for final ovulation. In view of the direct involvement of FSH levels in determining litter size it is probably not surprising that many regulatory mechanisms are available in order to maintain these levels within narrow limits. Ovarian oestradiol and inhibin are probably the most active FSH suppressive factors throughout the menstrual cycle. As the final result of several regulatory mechanisms the course of FSH throughout the cycle is characterized in general by a persistingly low level but with a subtle early follicular rise for induction of follicular growth and a mid-cycle surge. The periods with low levels, ensuring periodical monofollicular growth, correlate closely with oestradiol and the inhibins [17].
Next to the already mentioned conditions, several other additional situations in the reproductive years in the life of the female can be deduced in which FSH levels are also incidentally elevated. Theoretically, this could lead to multiple follicle growth, ovulation and thus twinning. In this contribution we briefly summarize these conditions and possible connections to twinning.
Section snippets
Hypothesis
The deduction of certain conditions with incidentally elevated FSH secretion is based on the following hypothesis: Re-initiation of the activity of the hypothalamic pituitary ovarian axis (HPO-axis) after a period of prolonged quiescence is characterized by overshoot secretion of FSH in temporary absence of fully operational gonadal feedback by oestrogens and inhibins.
The most frequently occurring prolonged silence of the HPO-axis is the prepubertal period. At birth, the system is entirely
Lactational amenorrhea
A first physiological cause of prolonged quiescence of the HPO-axis is the lactational amenorrhea which is typically the result of arrest of the hypothalamic GnRH pulse generator [20]. Indeed, Burger et al. [21]showed a remarkable overshoot of FSH secretion about 60 days post partum in women of whom some were already recovering from the lactation amenorrhea. It appeared that highest FSH levels were associated with lowest possible levels of mainly oestrogen but also inhibins (Fig. 3). Whether
Weight loss amenorrhea
The next condition mimicking puberty might be the recovery from hypothalamic amenorrhea after weight loss. The cause of weight loss amenorrhea is entirely attributable to deficient activity of the GnRH pulse generator [22]. The recovery results from re-initiation of this system. Currently, there are no data available that prove that FSH hypersecretion occurs under these circumstances. On the other hand, it was demonstrated by Braat et al. [23]that induction of ovulation with exogenously
Oral contraceptives
Finally, a frequently occurring condition with prolonged suppression of the activity of the HPO-axis in normal women is with the use of oral contraceptives [26]. In line with the proposed puberty mimicking hypothesis, it is expected that the first spontaneous cycle(s) are associated with higher FSH levels. Higher FSH levels were recently demonstrated in the follicular phase of the first spontaneous cycles after discontinuation of oral contraceptives in comparison to matched women that had never
Summary
In summary, we have tried to broaden the view on why under certain circumstances an increase in twinning rate may occur based on the assumption that an elevated FSH level is the principal underlying mechanism in DZ twinning. It is hypothesized that recovery from prolonged hypothalamic amenorrhea in part mimics hormonal sequelae of puberty characterized by temporary overshoot of FSH levels. By deduction, such conditions are recovery from lactational amenorrhea, recovery from use of oral
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