Female Infertility

Author: cristina guiotto
Date: 13/06/2012


For female infertility means the inability to carry a pregnancy in a woman able to conceive.

The menstrual cycle is regulated by complex interactions between the hypothalamic-pituitary-ovary and uterus. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) which stimulates the pituitary to release FSH and LH, which in turn stimulate the ovaries to release an oocyte able to be fertilized. At the same time the ovary secretes hormones that change the endometrial surface so as permit the installation.
GnRH is the main initiator of reproduction. Estradiol and other regulatory factors increase the sensitivity to the pituitary GnRH, which leads to a rapid increase of LH (LH surge) which promotes ovulation. After the rupture of the follicle, the corpus luteum secretes progesterone, which reduces the pulsatile GnRH. When progesterone levels fell again increases the frequency of GnRH pulses favoring the release of FSH and the maturation of a new follicle.
The ovarian cycle is divided into a follicular phase and a luteal phase. The first is characterized by the growth of the dominant follicle and ovulation, takes on average 10-14 days, even if the length of this phase is variable. The luteal phase begins after ovulation and represents the period in which the ovary secretes the hormones essential for proper implantation of the fertilized; this phase is relatively constant and lasts on average 14 (12-15) days.

Hypothalamic Amenorrhea

Several genetic lesions have been reported and believed to be responsible for GnRH deficiency.
The most common causes are, however, based on endocrine. The functional hypothalamic amenorrhea is characterized by a reduced release of GnRH that lead to low levels of FSH and LH with consequent anovulation.
Leptin, a hormone produced by adipocytes has been implicated in the development of this disorder. is a hormone that regulates the satiety, but it is also necessary for the maturation of the reproductive system, since receptors were found in the hypothalamus and in the gonadotrope cells. This is supported by the fact that leptin may stimulate the pulsatility of GnRH and secretion of gonadotropins. Many studies suggest that women with functional hypothalamic amenorrhea have low leptin levels in serum when compared with women eumenorroiche, this relative difference would cause a release of GnRH altered with subsequent onset of functional amenorrhea.

Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls, 2012

Functional hypothalamic amenorrhea pathogenesis frequently remains unknown, but often the association with hypercortisolism suggests that it may be preceded by physical stress, strenuous exercise or poor nutrition. This form of amenorrhea is reversible. It 's interesting to note that factors that seem to correlate with the percentage of recovery are the body mass index and low levels of cortisol in patients who start the healing, ovulation is preceded by a return within the normal limits of cortisol. However, if the onset of amenorrhea occurs during the period of maturation of the HPO peripuberale, recovery is less frequently total. The diagnosis of functional hypothalamic amenorrhea may be placed if the FSH / LH ratio is greater than 1 in the presence of ipoestrogeninemia. A minor alteration of hypothalamic function, however, can occur with normal laboratory findings, a history that coincides with "stress", and a negative evaluation for other causes of anovulation.
There is a case in which the low concentrations of cortisol lead to problems on fertility. It is of congenital adrenal hyperplasia , or adreno genital syndrome, hereditary disease that affects both sexes. Is caused by a genetically transmitted enzyme deficiency, which affects the synthesis of two important hormones: cortisol and aldosterone, produced in the adrenal glands.
In the most frequent genetic alteration is the enzyme 21-hydroxylase deficiency. The 21-hydroxylase is responsible for one of the step leading to the synthesis of cortisol and aldosterone; the deficiency of the enzyme blocks so the "assembly line" that normally leads to production of these hormones, causing reduced synthesis.
Consequently, they accumulate the intermediate compounds, which should be processed by the enzyme. The main of these is 17-hydroxy progesterone. The pituitary gland also records the absence of circulating cortisol and produces ACTH, which stimulates the adrenal glands to begin the stages of production of cortisol . ACTH stimulated the glands become enlarged (hyperplasia of the adrenal gland) and enhance the assembly of cortisol, thus aggravating the accumulation of 17-hydroxy progesterone. From 17-hydroxy progesterone also derive the male sex hormones (androgens), so the accumulation of 17-hydroxy progesterone leads to an increase of androgens, which can lead to virilization, that is the tendency, even for the females, to acquire sexual characteristics male.
Successful pregnancy after the treatment of primary amenorrhea in a patient with non-classical congenital adrenal hyperplasia, 2012

The athletes have demonstrated a hypothalamic dysfunction. These patients have a low amount of adipose tissue, often below the tenth percentile is therefore clear that there is a negative correlation between body fat and menstrual regularity. A minimal amount of body fat must be present for the proper functioning of the reproductive system. Several studies have shown that these amenorrheic athletes have lower serum levels of leptin, suggesting a role of this hormone as a mediator between nutritional status and reproductive system. The intense and prolonged exercise in which athletes are subjected amplifies the effect of nutritional deficiency: This synergism suppresses GnRH reducing the levels of estradiol.

Amenorrhea is often associated with eating disorders. One of the diagnostic criteria of anorexia nervosa is the absence of menstrual cycles for more than three months. The neuro-endocrine dysfunction is similar but often more severe than that described in association with functional hypothalamic amenorrhea. The severe reduction of the pulsatility of GnRH leads to suppression of LH and FSH levels (often undetectable) and results in anovulation and reduced serum levels of estradiol. Furthermore, given the intense endocrine and metabolic stress faced by these individuals, the hypothalamic-pituitary-adrenal axis is activated: the circadian adrenal secretion is maintained, but both the production of cortisol and plasma cortisol levels are persistently high in due to increased pituitary ACTH production.
Leptin levels are significantly lower than in healthy subjects and correlate with the percentage of fat and body weight. The increased levels of leptin in response to a correct diet involves a consequent increase of gonadotropins. Although this may suggest a role for leptin as a potential mediator between energy reserves and reproductive system. It's 'also altered the metabolism of thyroid hormones: TSH and T4 are the lower limits of normal range, but T3 levels are usually below the norm. This is attributable to reduced peripheral conversion of T4 to T3 and increased conversion of T4 to rT3, metabolically inactive thyroid hormone, this transformation is also observed in other states of severe nutritional deficiency and may be a protective mechanism in which a state of relative hypothyroidism reduces the basal metabolic functions in response to an increased catabolic state.

Endocrine disorders & female infertility, 2011

Pituitary Amenorrhea

Rare mutations can cause autosomal recessive deficiency of FSH, LH, TSH, prolactin and GH. Clinical manifestations include delayed puberty, signs of hypoestrogenism and infertility. A gene mutation of the GnRH receptor can result in a deficiency of FSH and LH.

Hyperprolactinemia is a common cause of amenorrhea, although the underlying mechanism is not fully understood, studies show that prolactin can interfere with the reproductive system in several ways. Receptors for prolactin have been identified in GnRH-secreting neurons, where they can directly suppress the secretion. The most reliable data reported in the literature appear to give effect to such a major role in the genesis of amenorrhea. There is also evidence of how the pituitary GnRH receptor are able to down-regulate in the presence of hyperprolactinemia. Furthermore, the prolactin level may act on ovarian, altering the secretion of progesterone and the synthesis of estrogens. In a patient with amenorrhea, hyperprolactinemia is defined the presence of prolactin levels above 20 ng / ml.
The normal release of prolactin following a circadian rhythm dictated by sleep, but prolactin can also be secreted in response to stress, exercise, stimulation of the breast or meal. Other causes of hyperprolactinemia are represented by drugs such as oral contraceptives, neuroleptics, tricyclic antidepressants, metoclopramide. Persistently high levels of prolactin may also be present in primary hypothyroidism.

Ovarian Amenorrhea

Have identified several mutations able to impair gonadal function and include alterations in receptor and steroidogenesis. Other causes lie in the type of autoimmune ovarian damage, and that the iatrogenic idiopathic. However, no identifiable specific causes in more than half of patients with premature ovarian failure.
The ovarian failure is characterized by amenorrhea with evidence of high levels of FSH (> 40 IU / L) and may occur at any period of life. If occurs before age 40 is also called the early menopause. Menopause is preceded by the loss of reproductive capacity and you think that the interval between the end of the fertile period and the beginning of menopause is about 10 years.
The anovulation however, most common cause of amenorrhea during the reproductive age, ovarian insufficiency differs in that it is possible that oocytes remain in the ovary. To determine anovulatory endocrine disorders are often characterized by an imbalance between androgens and estrogens, which involves an inappropriate mechanism for feedback and anovulation. Polycystic ovary syndrome is the state of anovulation secondary to hyperandrogenism most common.
A relationship between insulin and hyperandrogenism has been suggested based on severale observations Insulin and hyperandrogenism in women with polycystic ovary syndrome, 2010.

Several studies have observed that hyperinsulinemia is common in women with PCOS, as it should be determined by insulin resistance and how dysfunction in the system is responsible for signal transduction. The presence and degree of hyperinsulinemia in PCOS are amplified in the presence of obesity. Insulin can cause hyperandrogenism by acting at different levels, although the exact mechanism has not yet been well defined. In any case, in studies in which it is provided to the infusion of insulin, there was no observed increase in levels of testosterone, as well as there has been no change in buoyancy androgenic normal women undergoing treatment insulin-sensitizing. This shows that the effect of insulin on androgen production is much more likely a modulatory effect than a predisposing agent.
The insulin may act for example as a modulator of androgenic levels; several studies have shown that it is able to reduce the production of SHBG (sex hormone binding globulin). A reduction in insulin levels, through an increase of SHBG is able to reduce the share of bioavailable androgens.
Another related disease in 80% of patients with menstrual irregularities is Cushing's syndrome. We've already seen how the increase of androgens can have harmful effects on ovulation. It 'well known such as glucocorticoids are able to suppress the hypothalamic-pituitary axis, thus making hypercorticism may be an aggravating factor in the pathophysiology dell'anovulazione associated with this syndrome.

Obesity is often associated with menstrual irregularities and the relationship between these two situations is greater the earlier the onset of obesity. Alterations in the metabolism of steroids are clearly evident in obese women and are represented by reduced gonadotropin secretion that occurs with anovulation. The free testosterone levels tend to be the upper limit of normal for lower levels of SHBG. A share of androgen metabolism occurs in adipose tissue. Excess adipose tissue aromatize these androgens and increases the circulating estriol determining a situation of hyperestrogenism functional.
In fact, studies have shown that the percentage of conversion of androstenedione to estrone is correlated with the body weight. Other studies have shown that the conversion of estrone to estradiol in adipose tissue is higher in visceral fat than subcutaneous fat. The increase in visceral fat associated with obesity is also associated with hyperinsulinemia, which as we have seen, can have independent effects on ovarian function.

The reproductive abnormalities associated with hypothyroidism or hyperthyroidism, which consist of menstrual abnormalities, infertility and miscarriages.
Excess thyroid hormone has an impact on sex steroids. Thyroid hormones stimulate the hepatic production of SHBG in fact, and as a result there is an increase of the total values of estradiol, estrone, testosterone and dihydrotestosterone, although the levels of free hormones are included in the normal range. The metabolic clearance hormone is altered and this is partly due to the increase of the protein binding. The rate of conversion of androstenedione to estrogen and testosterone is increased, but the significance of these alterations is still unclear. It's possible that weight loss and other disorders related to hyperthyroidism may contribute to menstrual disturbances.
Conversely low levels of thyroid hormones lead to a decrease in the production of SHBG, with decrease of total concentrations of estradiol and testosterone. On more than one third of patients with primary hypothyroidism is hyperprolactinemia, and may think that this gives an important contribution to alterations of the cycle. Have also been investigated alterations in the levels of FSH and LH, and various studies suggest that this is not the peak at half of the cycle.
More generally if it's just an alteration of menstruation is prudent to perform a thyroid function.

Finally, a hint at the role that reactive oxygen species on female fertility.
It was shown as an excess of antioxidants is associated with infertility. In particular, an Israeli study coordinated by Nava Dekel of the Weizmann Institute of Science in Rehovot Reactive oxygen species are indispensable in ovulation, 2011 explains how to take high doses of antioxidants, like vitamins A, C and E, can be counterproductive especially for women, which may have fertility problems . Female mice were examined, a portion of which had been injected with massive doses of antioxidants. The treated mice showed a probability of ovulation much smaller than the other, probably because antioxidants from the body eliminate free radicals, molecules associated with aging but also to sustain the fertility.
Most likely these molecules are involved in ovulation cause inflammation and causing an integral part of the process.
On this basis also the unwitting assumption of antioxidants contained in foods and drinks at the end of the storage can be detrimental to fertility.

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