How is a dominant follicle selected?

Estrogen negative feedback and estrogen mediated FSH receptor formation help selecting a dominant follicle

Selecting a dominant follicle is a necessity because human uterus is designed for one baby 

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Medical student Jenna observed one of our patients having an ultrasound exam. She saw many small follicles (antral follicles) in both ovaries. She asks how the dominant follicle is selected. 

Unlike mice (pigs and other animals) that produce litter of multiple offspring, most human babies are single births. The reason for the difference becomes obvious when we examine the human uterus and mouse uterus side by side (see figure below). As a result, women normally release one egg each month. However, multiple gestation does happen in humans (either from two or more eggs or embryo splitting), its outcome is usually not as good as that of a single gestation.

The beginning of menstruation marks the beginning of growth of a new group of follicles. Among the many follicles (antral follicles) visualized, only one releases its egg. The remainder, with eggs inside them, becomes atretic. A dominant follicle is normally selected by cycle day 8 in a typical 28-day menstrual cycle.  

A girl has 2,000,000 eggs at birth and 300,000 – 400,000 at puberty. Eggs are in follicles. Follicles, based on their response to gonadotropin, FSH, can be divided into two stages: gonadotropin-independent and gonadotropin-dependent stages. They develop from the former to the latter constantly, even during pregnancy. Follicles at the latter stage is also called antral follicles; they are usually 9 mm (or smaller) and can be visualized by a trans-vaginal ultrasound.  

As mentioned above, follicles progress from FSH-independent to FSH-dependent stage at all time, including during pregnancy. Once they become FSH-dependent, they either continue to grow (if FSH is present) or become atretic. Most of the follicles become atretic.

Thanks to rising FSH at the beginning of menstruation, follicles that are FSH-dependent (i.e., antral follicles) gain momentum to grow. Those reaching FSH-dependent stage but miss this window of time become atretic, and are forever lost - 1,000 eggs are lost every month starting at puberty.  

The selection of a dominant follicle is achieved by the synergistic effort of (1) estradiol negative feedback, and (2) estradiol mediated FSH receptor increase. Relative to small antral follicles, large antral follicles produce more estradiol (because they have more granulosa cells). Since estradiol promotes the formation of FSH receptor, large antral follicles (which produce more estradiol) have more FSH receptors than their smaller counterparts.  

More FSH receptors allow large follicles to survive and continue to grow in a low FSH environment. The latter is caused by the rising estradiol and the estrogen negative feedback. What begins as a competition for survival between larger and smaller follicles gradually morphs into a competition amongst the larger follicles. Eventually, only one follicle survives the extremely low FSH environment. 

Antral follicle destined to become a dominant follicle is the follicle that is the right size (FSH-dependent) at the right time. Initially, it capitalizes on the rising FSH during the early follicular phase. Later, through estrogen negative feedback, it capitalizes on the lowering FSH levels. As time passes, those “less fortunate” follicles fall behind furthermore. These follicles are doomed from the beginning; they do not have a chance. 

The above works well in most instances. However, humans are not robots. The “control” of releasing one egg at a time is not 100%. Fortunately, “failure” is not common: the incidence of paternal (fraternal) twins is 1/250 to 1/300 frequency, and that of paternal triplets 1/9,000.