Subtle disorders of the menstrual cycle in subfertile and aging women

Abstract

Why do some women fail to become pregnant although they have regular menstrual cycles? Why does female fertility decrease with age? In this thesis, several groups of women have been investigated. We examined the growth of ovarian follicles by ultrasound, and we followed the concentrations of some hormones during the cycles of the following groups of women:

(1) Women who wished to conceive a pregnancy, but did not succeed to do so after at least one year. (2) Women with an amenorrhea or oligomenorrhea (cycles with a mean length > 6 weeks), who were treated with a drug, clomiphene citrate (CC) to stimulate follicle development and ovulation. (3) Healthy women of an age range (41-46 years) in which fertility is usually greatly diminished.

The cycles were compared with those of control groups.

We concluded that abnormal cycles occur more often (5% in contrast to almost none) in patients of group (1). In the majority of these cycles, the follicle has a normal growth pattern, but, after the signal that is supposed to induce ovulation, no rupture of the follicle occurs: so-called ‘luteinized unruptured follicle’ or ‘LUF’ cycles. It is not certain whether such ‘subtle ovulation disorders’ (‘SOD’) do occur repeatedly in the cycles of one woman, but this is probably so, because it was found that relatively low progesterone concentrations in blood can predict an SOD in a subsequent cycle. However, diagnosing such disorders is expensive, and makes it necessary for the patient to visit the hospital frequently. After treatment with drugs that are generally used to induce follicle growth and ovulation, many women become pregnant. It is, however, unknown how many of these pregnancies would have been achieved without treatment. Treatment of amenorrheic or oligomenorrheic women with CC is generally assumed to result in less pregnancies (about 40% of the patients) than expected when the ovulation rate (about 80%) is considered. In 12 women from group (2) who showed follicle growth when treated with CC, only one cycle was abnormal showing a LUF. We concluded that SOD are an unlikely cause of the discrepancy between ovulation rate and pregnancy rate during CC treatment. Some, relatively older, women showed a temporary decline of the levels of serum estradiol (the hormone that is produced by growing follicles). The relevance of this finding is still not clear. Cycles of women from group (3) were compared with those of a younger age-group (22-34 years). SOD, as a possible cause of declining fertility with age, did not occur. The cycles of the older women were shorter, due to an earlier start of the development of a ‘dominant’ follicle (the follicle that is destined to ovulate). The development of such dominant follicles already started during the second half (luteal phase) of the preceding cycle. Until now it has been supposed that the cycles of older women are shorter due to a speeding-up of the growth of a dominant follicle (‘accelerated’ growth), instead of such an ‘advanced’ follicle growth. The earlier start of the development of a dominant follicle possibly occurs during a less favourable hormonal environment, which could be detrimental for the follicle, and for the oocyte it contains.