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Classification

There are two primary ways to classify amenorrhoea. Types of amenorrhoea are classified as primary or secondary, or based on functional "compartments" (Speroff).[2] The latter classification relates to the hormonal state of the patient, which could be hypo-, eu-, or hypergonadotropic (whereby an interruption in the communication between gonads and FSH causes FSH levels to be either low, normal or high).

Types of Amenorrhea

By primary vs. secondary: Primary amenorrhoea is the absence of menstruation in a woman by the age of 16.[3] As pubertal changes precede the first period, or menarche, women by the age of 14 who still have not reached menarche, plus having no sign of secondary sexual characteristics, such as thelarche or pubarche—thus are without evidence of initiation of puberty—are also considered as having primary amenorrhoea.[4] Secondary amenorrhoea is where an established menstruation has ceased—for three months in a woman with a history of regular cyclic bleeding, or nine months in a woman with a history of irregular periods. This usually happens to women aged 40–55. However, adolescent athletes are more likely to experience disturbances to the menstrual cycle than athletes of any other age . Amenorrhoea may cause serious pain in the back near the pelvis and spine. This pain has no cure, but can be relieved by a short course of progesterone to trigger menstrual bleeding.

Hypothalamic Amennorhea

Women who perform considerable amounts of exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic (or 'athletic') amenorrhoea. Functional Hypothalamic Amenorrhea (FHA) can be divided into three categories of cause: stress, weight loss and excessive exercise. It was thought for many years that low body fat levels and exercise related hormones (such as beta endorphins and catecholamines) disrupt the interplay of the sex hormones estrogen and progesterone. However, recent studies have shown that there are no differences in the body composition, or hormonal levels in amenorrhoeic athletes as compared to regularly cycling athletes[citation needed]. Instead, amenorrhoea has been shown to be directly attributable to low energy availability. Many women who diet or who exercise at a high level do not take in enough calories to expend on their exercise as well as to maintain their normal menstrual cycles.[8] The difference between excersise and weight loss-induced symptoms is difficult to distinguish, as the overall trigger pertains to an insufficient storage of fat, necessary for hormone production. Instead, amenorrhoea has been shown to be directly attributable to low energy availability. Many women who diet or who exercise at a high level do not take in enough calories to expend on their exercise as well as to maintain their normal menstrual cycles.[6] In such cases, ghrelin acts as a metabolic signal and detects abnormal body weight or unsuitable eating habits, and inhibits the hypothalamic-pituitary-ovarial axis. Elevated concentrations of ghrelin alter the frequency and amplitude of GnRH pulses, which causes diminished pituitary release of LH and follicle-stimulating hormone (FSH), hormones that maintain normal ovulation. The altered interaction between ghrelin and the hypothalamic-pituitary-ovarial axis (also referred to as the hypothalamic-pituitary-gonadal axis) is also responsible for the prolongation of amenorrhea in subjects who have regained normal weight.

Additional neuropeptides, neurotransmitters and neurosteroids that act as regulators of GnRH pulsatile secretion are suspected to change in response to energy deficiency, caused by all three conditions of FHA. These include allopregnanolone, neuropeptide Y, corticotropin-releasing hormone, leptin and beta-endorphin, all of which contribute to the pituitary secretion of GnRH.

Women with eating disorders, such as anorexia nervosa are likely to suffer from secondary amenorrhoea. This can be attributed to low levels of the hormone leptin. [7] A critical leptin level is necessary to maintain regular menstrual cycles, and eating disorders decrease the amount of leptin circulating in a woman's body. Like ghrelin, Leptin also acts as a transmitter of energy deficiency, informing the reproductive axis of the body's fat stores. Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing. Thus, women who suffer from FHA but maintain a normal weight experience less severe menstrual irregularities than under-wheight amenorrheic patients.

Treatment

Treatments vary based on the underlying condition. Key issues are problems of surgical correction if appropriate and oestrogen therapy if oestrogen levels are low. For those who do not plan to have biological children, treatment may be unnecessary if the underlying cause of the amenorrhoea is not threatening to their health. However, in the case of athletic amennorhea, deficiencies in estrogen and leptin often simultaneously result in bone loss, which can prove highly detrimental to a patients overall bone structure, causing irreversible damage that could correlate to long term infertility. Unless receiving eggs from an egg donor or in vitro fertilization, a woman is unable to conceive while she is amenorrhoeic. On the other hand, 'athletic' and drug-induced amenorrhoea has no effect on long term fertility as long as menstruation can recommence. The best way to treat 'athletic' amenorrhoea is to decrease the amount and intensity of exercise; but weight recovery, or increased rest does not always catalyze the return of a menses. Recommencement of ovulation suggests a dependency on a whole network of neurotransmitters and hormones, altered in response to the initial triggers of secondary amennorrhoea. To treat drug-induced amenorrhoea, stopping the medication on the advice of a doctor is a usual course of action.

Looking at Hypothalamic amenorrhea, studies have provided that the administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA abnormalities related to the condition of stress-related amenorrhea. This involves the repair of the PI3K signaling pathway, which facilitates the integration of metabolic and neural signals regulating gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH). In other words, it regulates the neuronal activity and expression of neuropeptide systems that promote GnRH release. However, SSRI therapy represents a possible hormonal solution to just one hormonal condition of Hypothalamic Amenorrhea. Furthermore, because the condition involves the inter workings of many different neurotransmitters, much research is still to be done on presenting hormonal treatment that would counteract the hormonal affects.

As physiological treatments to hypothalamic amenorrhoea, injections of R-metHuLeptin have been tested as treatment to oestrogen deficiency resulting from low gonadotropins and other neuroendocrine defects such as low concentrations of thyroid and IGF-1. R-metHuLeptin has appeared effective in restoring defects in the hypothalamic-pituitary-gonadal axis and improving reproductive, thyroid, and IGF hormones, as well as bone formation, thus curing the amenorrhoea and infertility. However, it has not proved effective in restoring of cortisol and adrenocorticotropin levels, or bone resorption.