Why are anovulatory cycles with irregular menstrual cycles due to Follicle-Stimulating Hormone (FSH) deficiency rather than Luteinizing Hormone (LH) deficiency?

Why Anovulatory Cycles Are Due to FSH Deficiency Rather Than LH Deficiency

Anovulatory cycles with irregular menstruation are fundamentally caused by FSH deficiency (or inadequate FSH action) because FSH is the primary hormone responsible for follicular recruitment, growth, and maturation to the point of dominant follicle selection—without adequate FSH, follicles cannot develop sufficiently to ovulate, regardless of LH levels. 1, 2

The Critical Role of FSH in Follicular Development

FSH is the rate-limiting hormone for folliculogenesis:

• FSH drives the initial recruitment and growth of antral follicles from the primordial follicle pool, which is essential for any follicle to reach the stage where it can respond to LH 3, 1
• Without adequate FSH stimulation during the early-to-mid follicular phase, follicles cannot mature to the preovulatory stage, making LH action irrelevant since there is no mature follicle for LH to trigger ovulation 4, 1
• The FSH threshold must be exceeded for follicular development to proceed—studies demonstrate that even when LH is present, insufficient FSH prevents follicular maturation 5, 4

Why LH Deficiency Alone Does Not Cause Anovulation

LH plays a secondary role that only becomes critical after FSH has done its work:

• LH is primarily responsible for the ovulatory trigger and luteinization of the mature follicle, not for the initial follicular development 5
• In functional hypothalamic amenorrhea (FHA), reduced GnRH pulsatility leads to decreased LH pulse frequency AND reduced FSH levels, but the FSH reduction is what prevents folliculogenesis 6
• Research shows that women with severe LH deficiency (LH <1.2 IU/L) can still achieve follicular development with FSH supplementation alone, demonstrating that FSH is sufficient for folliculogenesis even when LH is profoundly low 5

The FSH Threshold Concept

A critical FSH threshold must be maintained throughout the follicular phase:

• Blunted FSH elevation during the luteal-follicular transition is specifically associated with luteal phase deficiency and anovulation in exercising women, indicating that inadequate FSH rise prevents proper follicular recruitment 1
• Even low-dose exogenous FSH (75 IU/day) started as late as cycle day 7 can rescue follicular development, proving that FSH availability is the limiting factor for ovulation 4
• In polycystic ovary syndrome (PCOS), the most common cause of chronic anovulation, the primary therapeutic intervention is FSH administration—clomiphene-resistant PCOS patients respond to low-dose FSH given in a stepwise fashion 2

The Pathophysiology in Functional Hypothalamic Amenorrhea

FHA illustrates why FSH deficiency is the culprit:

• Slow GnRH pulse frequency in FHA leads to decreased LH secretion and, to a lesser extent, FSH secretion, since reduced GnRH pulsatility actually favors FSH over LH secretion 6
• Despite this relative preservation of FSH compared to LH, folliculogenesis still fails, indicating that even modest FSH reductions are sufficient to prevent ovulation 6
• Exogenous pulsatile GnRH administration restores ovulatory function by normalizing both FSH and LH, but the restoration of FSH is what enables follicular development to resume 6

Clinical Evidence Supporting FSH as the Primary Deficiency

Multiple lines of evidence confirm FSH's primacy:

• In perimenopause, FSH rises first (due to declining inhibin B from reduced follicle numbers) while ovulatory cycles can still occur intermittently, demonstrating that FSH availability determines ovulatory capacity 3
• Inhibin B, produced by small antral follicles, is the major regulator of FSH secretion—when follicle numbers decline, inhibin B falls, FSH rises compensatorily to maintain follicular development 3
• The age-related decrease in primordial follicle numbers leads to decreased inhibin B, which causes FSH elevation as a compensatory mechanism to maintain estradiol production 3

Common Pitfall to Avoid

Do not assume that because both FSH and LH are low in hypogonadotropic hypogonadism, they are equally responsible for anovulation:

• FSH deficiency prevents follicles from ever reaching the stage where LH can act 5, 4
• LH supplementation without adequate FSH will not induce ovulation, whereas FSH alone (even with very low LH) can achieve follicular development in many cases 5
• The LH threshold for follicular development is much lower than commonly appreciated—basal LH levels as low as 1.2-1.6 IU/L may be sufficient if FSH is adequate 5