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Anovulation causes and pathogenesis

Anovulation is a very common problem which presents itself in a variety of clinical manifestations, including amenorrhea, irregular menses, and hirsutism. Serious consequences of chronic anovulation are infertility and a greater risk for developing carcinoma of the endometrium and the breast. The physician must appreciate the clinical impact of anovulation and undertake therapeutic management of all anovulatory patients to avoid these unwanted consequences. 

Why does Anovulation occur? 

Normal ovulation requires coordination of the menstrual system at all levels, the central hypothalamic-pituitary axis, the feedback signals, and local responses within the ovary. The loss of ovulation may be due to any one of a variety of factors operating at each of these levels. The end result is a dysfunctional state: anovulation. In this article, we will discuss the variety of mechanisms by which dysfunction of the ovulatory cycle can occur and how the clinical expressions of the resulting abnormal menstrual function are produced.

Pathogenesis of Anovulation

During menses, escape from the negative feedback of estrogen results in increased follicle stimulating hormone (FSH) secretion by the anterior pituitary. 

This initial increase in FSH is essential for follicular growth and steroidogenesis. 
With continued growth of the follicle, estradiol production within the follicle maintains follicular sensitivity to FSH allowing conversion from a microenvironment dominated by androgens to one dominated by estrogen, a change necessary for a complete and successful follicular life span.

Continuing and combined action of FSH and estradiol leads to the appearance of luteinizing hormone (LH) receptors on the granulosa cells, a prerequisite for luteinization and ovulation. 

Ovulation is triggered by the rapid rise in circulating levels of estradiol. 
A positive feedback response at the level of the anterior pituitary results in the midcycle surge of LH necessary for expulsion of the egg and formation of the corpus luteum. 

A rise in progesterone follows ovulation along with a second rise in estradiol, producing the well-known 14day luteal phase characterized by low FSH and LH levels. 

The demise of the corpus luteura, concomitant with a fall in hormone levels, allows FSH to increase again, thus initiating a new cycle. 

This recycling mechanism is regulated largely by estradiol
The negative feedback relationship between estradiol and FSH results in the critical initial rise in that gonadotropin during menses, and the positive feedback relationship between estradiol and LH is the ovulatory stimulus. 

Within the ovary, estradiol induces follicular receptor responses necessary for growth and function. Estradiol is, therefore properly viewed as the critical agent for appropriate hypothalamic-pituitary-ovarian responses. 

Dysfunction in the cycle may be due to an abnormality in one of the various roles for estradiol, or an inability to respond to estradiol signals. Problems in normal function may be conveniently organized into central defects, abnormalities in the feedback signals, and abnormal function within the ovary itself.

Central Defects

The hypothalamic-pituitary axis may be unable to respond, even if given adequate and appropriately timed feedback signals. 

A pituitary tumor represents an obvious example of a central defect in menstrual function, and is discussed in Chapter of "Amenorrhea".
Although difficult to demonstrate definitively, malfunction within the hypothalamus is both a likely, as well as a favorite, explanation for ovulatory failure. 

Normal pituitary ovulatory response to the follicle's steroid signals requires the presence of gonadotropin releasing hormone (GnRH) pulsatile secretion within a critical range.

The teenager between menarche and the onset of ovulation cannot generate a normal cycle until full GnRH pulsatile secretion is achieved. 

Increasing intensity of GnRH suppression is associated with increasing dysfunction and changing clinical presentation. 

A variety of problems, such as stress and anxiety, borderline anorexia nervosa, and acute weight loss after a crash diet are thought to inhibit norrnal GnRH pulsatile secretion so that the gonadotropin surge is not possible and only homeostatic pituitary-ovarian function is maintained. 

At least one specific clinical syndrome has been recognized: hyperprolactinemia
Increasing levels of prolactin can cause a woman to progress through a spectrum, beginning with an inadequate luteal phase to anovulation to the amenorrhea associated with complete GnRH suppression.

A search for galactorrhea and measurement of the prolactin level are important screening procedures for all women who are not ovulating normally.

Abnormal signals

Abnormal cycles can be due to failures within the system, or due to the introduction of confounding factors. It is instructive to focus on the blood estradiol concentration as the critical signal for the machinery of the ovulatory cycle. 

In order to achieve the appropriate changes within the cycle, estradiol levels must rise and fall in synchrony with morphologic events. Therefore, two possible signal failures may occur: 

  • Estradiol levels may not fall low enough to allow sufficient FSH response for the initial growth stimulus.
  • Levels of estradiol may be inadequate to produce the positive stimulatory effects necessary to induce the ovulatory surge of LH. 

1. Loss of FSH Stimulation:
In order to achieve recycling, a nadir in blood sex steroid levels must occur so that the initial event in the cycle, the rise in FSH, may take place. 

Sustained estrogen at such a key moment would not permit FSH stimulation of follicular growth and maturation, and recycling would be thwarted. The necessary decline in blood estrogen requires reduction of secretion, appropriate clearance and metabolism, and the absence of a significant contribution of estrogen to the circulation by extragonadal sources.

Persistent Estrogen Secretion: The most common clinical example of anovulation associated with continued secretion of estrogen is pregnancy. Persistent and elevated secretion of estrogen canencountered rarely with an ovarian or adrenal tumor. In such a case, anovulation or amenorrhea mayGing the patient to a physician's attention.

Abnormal Estrogen Clearance and Metabolism: The clearance and metabolism of estrogen can be impaired by other pathologic conditions, such as thyroid or hepatic disease. It is for this reason that a careful history and physical examination are important elements in the differential diagnosis of anovulation. Both hyperthyroidism and hypothyroidism can causepersistent anovulation by altering not only metabolic clearance, but also the peripheral conversion rates among the various steroids. 

The subtle presence of hypothyroidism, which may be associated with elevated prolactin levels, demands screening of anovulatory and amenorrheic women with a thyroid stimulating hormone (TSH) level.

Extraglandular Estrogen Production: Extragonadal contribution to the blood estrogen level can reach significant proportions. While the adrenal gland does not secrete appreciable  amounts of estrogen into the circulation, it indirectly contributes to the total estrogen level. This is accomplished by the extragonadal peripheral conversion of C-19 androgenic precursors, mainly androstenedione, to estrogen.

In this manner psychologic or physical stress may increase the adrenal contribution of estrogenic precursor, and subsequent conversion to estrogen may sustain the blood level of estrogen at a time when a decline is necessary for successful recycling of the menstrual cycle. Adipose tissue is capable of converting androstenedione to estrogen, hence the percent conversion increases with increasing body weight. This is at least one mechanism for the wellknown association between obesity and anovulation.

Loss of LH Stimulation:
 A failure in gonadal production of estrogen need not be absolute. Obviously the patient with gonadal dysgenesis and ovarian failure will present with amenorrhea and infertility because of a total lack of estrogen secretion.
More commonly, the clinician is concerned with the patient who has gonadotropin and estrogen production, but does not ovulate. The failure to achieve critical midcycle level of estradiol necessary to trigger the gonadotropin surge may be due to a relative deficiency in steroid production. The perimenopausal woman undergoes a terminal period of anovulation which may represent a steroidogenic refractoriness within the remaining elderly follicles. This inadequacy may be due to intrinsic weaknesses or an impairment in the follicular-gonadotropin interaction. In any case, the end result is the same, a failure to achieve critical signal levels of estradiol at the appropriate time in midcycle.

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