Anovulation

Updated: Dec 30, 2015
  • Author: Armando E Hernandez-Rey, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Overview

Background

Ovulation is the result of a maturation process that occurs in the hypothalamic-pituitary-ovarian (HPO) axis and is orchestrated by a neuroendocrine cascade terminating in the ovaries. Any alteration results in a failure to release a mature ovum, leading to anovulatory cycles. Anovulation may manifest in a variety of clinical presentations, from luteal insufficiency to oligomenorrhea.

Anovulation is a not a disease but a sign, in much the same way that polycystic ovaries are the manifestation of a much larger disease process.

Education for these patients should focus on an understanding of the underlying disorders to ensure compliance with both medical therapy and lifestyle modifications. For patient education resources, see Women's Health Center, as well as Anorexia Nervosa.

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Pathophysiology

To understand anovulation, one must 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. [1] 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. [2] 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. [2]

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. [3]

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. [4]

How polycystic ovary syndrome (PCOS) is associated with anovulatory cycles has not been completely elucidated. 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. [5] 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. [2]

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Epidemiology

Frequency

United States

Almost all women experience anovulatory cycles at some point in their reproductive lives. Yet, to attempt to determine the frequency of chronic anovulation in the general population is quite difficult because of underreporting. Estimates of chronic anovulation rates range from 6-15% of women during the reproductive years.

Interestingly, an article by Rasgon introduced a certain subset of the population as being at an increased risk for anovulatory disorders, stating that reproductive endocrine disorders, such as PCOS, hypothalamic amenorrhea, premature menopause, and hyperprolactinemia, are reportedly more common in women with epilepsy than in the general female population. The article further elaborates on the frequency of PCOS in patients who endure epilepsy independent of the use of antiepileptic therapy. [6] The risk of developing PCOS during valproate (VPA) treatment seems to be higher in women with epilepsy than in women with bipolar disorders; this might be due to an underlying neuroendocrine dysfunction. Gynecologists must be aware of the possibility that PCOS might be related to VPA use in this population of patients, and the risks and benefits of this treatment should be weighed in the presence of PCOS. [7]

Mortality/Morbidity

Prognosis is generally favorable with appropriate and timely treatment.

Morbidities associated with chronic anovulation include hyperinsulinemia, insulin resistance, early onset of type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, hypertension, infertility, endometrial hyperplasia, and endometrial cancer.

Complications

Complications of anovulation include the following:

  • Endometrial hyperplasia
  • Insulin resistance or type 2 diabetes mellitus
  • Cardiovascular disease
  • Venous thromboembolism secondary to estrogen therapy
  • Electrolyte derangements (anorexia nervosa)
  • Arrhythmias (anorexia nervosa)

Pregnancy complications

Women with PCOS who conceive are at increased risk for gestational diabetes, preeclampsia, cesarean delivery, and preterm and post-term delivery. Their newborns are at increased risk of being large for gestational age but are not at increased risk of stillbirth or neonatal death. [34]

Race

In one study, the frequency of anovulation was greater among white women (9 of 63 [14.3%]) than black women (4 of 56 [7.1%]) or Hispanic women (7 of 102 [6.9%]), although these differences were not statistically significant. [8]

Sex

Anovulation occurs only in women of reproductive age.

Age

Anovulation is physiologic at the extremes of reproductive age. During menarche, absence of ovulation is due to immaturity of the HPO axis, leading to an uncoordinated secretion of GnRH (pulsatility).

During perimenopause, ovarian factors and a dysregulation of feedback mechanisms are responsible.

When anovulation occurs outside of the perimenarchal or perimenopausal years, extrinsic and intrinsic causes must be excluded.

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