Question

A couple is having difficulty conceiving a baby. After various tests, it was found that the woman cannot ovulate. Describe endocrine alterations that could explain why she cannot ovulate. Ensure that you describe relevant tissues and feedback mechanisms in your answer.

Answer 1

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

To understand anovulation, you first understand what occurs during a normal ovulatory cycle. In normal physiology, ovulation is dependent on the presence of a functioning hypothalamic-pituitary-ovarian (HPO) axis. The arcuate nucleus within the hypothalamus is composed of a collection of neurons and, when stimulated, releases GnRH into the portal vessels of the pituitary stalk in a pulsatile fashion. GnRH stimulates receptors in the anterior pituitary gland to produce and secrete both LH and FSH. In women, FSH induces maturation of ovarian follicles and eventual production of estrogen, while LH modulates the secretion of androgens from the ovarian theca cells. Estrogen, in turn, produces negative feedback on the pituitary gland.

As the follicle grows through accumulation of follicular fluid, the cohort of granulosa cells acquire the necessary receptors to respond to LH with increased formation of cyclic adenosine monophosphate (cAMP). During the midcycle, the estrogen levels in the circulation reach a concentration that causes a positive feedback action on LH secretion. This is called the LH surge. Generally speaking, approximately 16-24 hours after the LH peak, ovulation occurs with the extrusion of a mature oocyte from the graafian follicle and the formation of the corpus luteum. These events are the culmination of a well-coordinated interplay between hormones and their appropriate receptors and proteolytic enzymes and prostaglandins acting in concert with one another, all directed by the HPO axis.

The system is so sensitive that even the slightest alteration in any of these factors can disrupt its fluidity and lead to anovulation.

When problems arise at any of the many different levels involved in the normal menstrual cycle, it is sometimes helpful to separate the levels by organ system. The hypothalamus and the anterior pituitary can be considered the neuroendocrine components by virtue of their proximity to each another, while the ovaries are a separate compartment. The third aspect that can be defective is the signaling process that occurs between these 2 areas.

The initial stimulus must come from the hypothalamus in the form of gonadotropin-releasing hormone (GnRH); this decapeptide must be secreted in a pulsatile fashion within a critical range. For example, sexual maturity is not attained until the onset of regular ovulatory cycles, which may take months to years to occur. This maturation process is orchestrated by a neuroendocrine cascade and modified by autocrine and paracrine events in the ovaries, in which GnRH is the principal mediator.

Any alteration in the GnRH pulse generator alters the hormonal milieu necessary for gonadotropin secretion and eventual response at the level of the ovary. Several entities (eg, hyperprolactinemia) are known to cause this type of dysregulation. Increasing levels of prolactin can cause a woman to progress from a deficient luteal phase to overt amenorrhea, usually associated with complete GnRH suppression. More common causes of dysregulation include stress, anxiety, and eating disorders, which are also associated with an inhibition of normal GnRH pulsatility through excessive hypothalamic activity of corticotrophin-releasing hormone and stimulation of beta-endorphins.

How polycystic ovary syndrome (PCOS) is associated with anovulatory cycles Two associations with this disease entity are theorized to be at least somewhat responsible for its development. The first is the persistent elevation of LH levels in these patients; the second is the apparent arrest of antral follicle development at the 5- to 10-mm stage and consequent failure to enter the preovulatory phase of the cycle. This evidence indicates that the disturbance is mainly a central defect that initiates the cascade of events leading to its onset.

Similarly, any condition, whether primary or secondary, that results in either a persistent elevation or an insufficient attainment of estrogen levels can inhibit ovulation through a disruption of the mechanisms that induce the LH surge. To achieve the corresponding changes within the cycle, estradiol levels must rise and fall appropriately.