The pathogenesis of amenorrhea is determined by the level of the neuroendocrine reproductive axis from which the disorder stems and, at every degree of the axis, whether it is due to a structural problem or to a functional issue of hormonal control.
In a previously menstruating affected individual presenting with amenorrhea, it's essential first to rule out pregnancy after which to assess thyroid purpose (serum TSH degree) and pituitary purpose (serum prolactin level) before approaching the workup of amenorrhea, compartment by compartment.
1. Uterine disorders-Scarring and damage towards the underlying stem cells from which the endometrium proliferates will guide to amenorrhea. In most instances, this occurs within the setting of endometritis right after curettage (scraping with the endometrium) possibly for postpartum bleeding or dysfunctional uterine bleeding.
To determine the presence of a functional endometrium, an amenorrheic affected individual is given possibly progesterone alone or the sequential combination of estrogen and progesterone. Renewed vaginal bleeding right after cessation of the hormonal treatment suggests that the endometrium is intact. This response also indicates how the cause of amenorrhea lies elsewhere (ie, is due to an endocrine defect causing absence or insufficiency of cyclic estrogen and progesterone stimulation).
2. Ovarian failure-Amenorrhea producing from ovarian failure could be either main or secondary to dysfunction higher in the female neuroendocrine reproductive axis. Primary ovarian failure happens having a premature loss of all follicles.
This can outcome from genetic disorders (chromosomal aberrations), autoimmune disorders (lymphocytic oophoritis), metabolic difficulties (galactosemia) or exogenous insults such as chemotherapy, toxins, or radiation. Secondary ovarian failure is caused by a lack of gonadotropin stimulation of otherwise regular ovaries, producing in failure to create the estrogen and progesterone needed for menstrual cycles.
a. Genetic causes-Genetic causes of ovarian failure consist of Turner's syndrome (abnormality in or absence of an X chromosome) and mosaicism (multiple cell lines of varying sex chroosome composition). Approximately 40% of patients who appear to have Turner's syndrome (short stature, webbed neck, shield chest, and hypergonadotropic hypoestrogenic amenorrhea) prove to become mosaics.
The presence of any Y chromosome in the karyotype of those individuals carries a high danger for gonadal germ cell tumors and is definitely an indication for gonadectomy. Therefore, a karyotype ought to be performed on any amenorrheic individual younger than 30 with high FSH and LH amounts.
b. Premature ovarian failure-Premature ovarian failure happens when atresia of follicles is accelerated in an ovary of a woman of reproductive age. It presents with symptoms and signs of menopause producing from estrogen deficiency at an inappropriately young age. LH and FSH amounts are increased. There is a lack of estrogen production and an absence of viable follicles.
In some situations, premature ovarian failure is just one manifestation of an autoimmune polyglandular failure syndrome by which autoantibodies destroy a quantity of different tissues, including the ovary. These sufferers also might have associated hypothyroidism, adrenal insufficiency, or pernicious anemia.
c. Long-term anovulation-Other patients are discovered to have sufficient numbers of follicles, but these fail to mature and ovulate. This situation is known as chronic anovulation and is also manifested as amenorrhea with intermittent bleeding (caused by uncoordinated overgrowth with the endometrium in response to stimulation by estrogen alone).
Left untreated, the high estrogen degree places these ladies at increased danger for endometrial carcinoma. Among the brings about of chronic anovulation is thyroid dysfunction. Both hyperthyroidism and hypothyroidism can alter ovarian purpose and also the metabolism of androgens and estrogens, producing inside a variety of menstrual disorders.
Another reason for chronic anovulation is hyperprolactinemia. It has been proposed that progressively a lot more severe hyperprolactinemia presents first as an inadequate luteal phase with recurrent abortion, then as anovulation with intermittent bleeding, and finally as amenorrhea.
d. Hormonal suggestions disorders-Disruption with the coordinated cyclical interaction between the ovary and also the brain can also lead to anovulation. This happens in patients with polycystic ovarian syndrome (PCOS), which impacts 2-5% of reproductive age women who present with amenorrhea and hirsutism. Patients are frequently obese with hyperinsulinemia with insulin resistance and dyslipidemia.
Additionally, they have elevated plasma androgens, with each other with increased plasma estrogens that are predominantly estrone derived from peripheral aromatization of adrenal androgens within the granulosa cell by the enzyme aromatase (cytochrome P450, loved ones 19, subfamily A, polypeptide 1, or CYP19A1).
The hyperinsulinemia is believed to be a key etiologic factor. Insulin outcomes in decreased hepatic synthesis of steroid hormone-binding globulin (SHBG) and insulin-like growth element binding protein-1 (IGFBP-1). The decreased amounts of binding proteins outcomes in an improve in free of charge androgens, estrogens, and IGF-1. IGF-1 and higher levels of insulin stimulate the IGF-1 receptor, leading to elevated thecal androgen production in response to LH, contributing towards the hyperandrogenemic state.
The high androgens favor atresia of building follicles and disrupt the suggestions relationships that normally outcome in selection of the dominant follicle for ovulation. The producing anovulation is associated with amenorrhea and estrogen-induced endometrial hyperplasia with breakthrough bleeding. The elevated estrogen amounts also are implicated in the improvement of endometrial cancer.
Thus, events occurring within the brain, ovary, and bloodstream of these sufferers work with each other to constitute a vicious cycle that maintains the aberrant feedback relationships. The high levels of androgens within the bloodstream are accountable for hirsutism. Patients with increased androgens from totally different causes (eg, Cushing's illness and congenital adrenal hyperplasia) also display amenorrhea associated with polycystic ovaries, suggesting that the structural changes within the ovaries are secondary towards the disordered suggestions.
e. Pituitary disorders-Head trauma resulting in pituitary stalk transection with loss of hypothalamic-pituitary communication ought to be regarded in patients with new-onset infertility with amenorrhea. The exact same is true of vascular accidents this kind of as Sheehan's syndrome, in which postpartum hemorrhage brings about hypotension and consequent ischemic necrosis of the pituitary.
Enlargement of the anterior pituitary throughout pregnancy might predispose to ischemia under conditions of hypotension. The pituitary around doubles in size throughout regular pregnancy, largely as a outcome of hypertrophy and hyperplasia of prolactin-secreting lactotrophs.
f. Hypothalamic disorders-Inputs from various central pathways impinge about the mediobasal portion with the hypothalamus, including the arcuate nucleus, from which GnRH pulses originate. Medications and illicit drugs that affect the neurotransmitters utilized in these pathways (opioids, dopamine, and norepinephrine) can, consequently, affect GnRH secretion as nicely. This underscores the significance of the getting a detailed medication and social background in the workup of amenorrhea.
Also important is really a detailed history of behavioral patterns or any recent life changes. Psychic stress (eg, that associated with moving to a various country) can lead to altered GnRH secretion and subsequent amenorrhea that lasts as much as 1 year. Vigorous physical exercise and excessive fat loss can also guide to impaired GnRH pulsatility, accounting for that amenorrhea observed in competitive athletes and in ladies with anorexianervosa.
Thus, a wide variety of elements that alter pulsatile release of GnRH can influence female reproductive physiology. Absence of menstrual periods due to a change in 1 of those elements is termed hypothalamic amenorrhea and is really a common cause of infertility. Correction with the underlying trigger often leads to some return of normal cyclic ovulation. If not, pulsatile GnRH therapy can reestablish the normal patterns of pituitary stimulation, receptor-mediated responsiveness, and suggestions, restoring fertility.
g. Indirect influences-In addition to factors that function directly about the GnRH-secreting neurons, indirect influences must be regarded. Main hypothyroidism, as nicely as main or secondary hyperprolactinemia, can outcome in altered GnRH pulse frequency and amplitude.
The subsequent diminished gonadotropin secretion produces a secondary ovarian failure and amenorrhea. Examples of problems that result in secondary hyperprolactinemia include lactation and treatment with drugs that have dopamine-blocking outcomes (eg, antipsychotic agents).