Functional hypothalamic amenorrhea pdf

Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 IGF-1 and low total triiodothyronine. Functional hypothalamic amenorrhea is related to profound impairment of reproductive functions including anovulation and infertility. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk. Therefore, osteopenia and osteoporosis are the main long-term complications of FHA. Cardiovascular complications include endothelial dysfunction and abnormal changes in the lipid profile.

FHA patients present significantly higher depression and anxiety and also sexual problems compared to healthy subjects. FHA patients should be carefully diagnosed and properly managed to prevent both short- and long-term medical consequences. Functional hypothalamic amenorrhea FHA is classified as hypogonadotropic hypogonadism related to an aberration of the pulsatile release of gonadotropin-releasing hormone GnRH from the hypothalamus [ 1 , 2 ].

The spectrum of hypothalamic—pituitary disturbances in FHA may be very broad and includes a lower mean frequency of LH pulses, the complete absence of LH pulsatility, as well as a normal-appearing secretion pattern and higher mean frequency of LH pulses [ 3 ]. In turn, decreased gonadotropin secretion leads to reduced estradiol production in the ovary.

Depending on the eliciting factor, there are three classes of FHA: weight loss related, stress related and exercise related [ 4 ]. Regardless of the specific trigger, a complex state of hypoestrogenism, other endocrinological aberrations and metabolic abnormalities due to FHA may impact the whole body homeostasis [ 5 ].

The incidence is higher in athlete women. DeSouza et al. The complex of distorted eating, amenorrhea and osteoporosis was first described in and is known as female athlete triad [ 8 ]. Functional hypothalamic amenorrhea should be, in each case, differentiated from other forms of primary or secondary amenorrhea. The basic approach to this distinction is an assessment of the gonadotropins and identifying hypogonadotrophic hypogonadism [ 6 ].

If such a diagnosis has been made, the key diagnostic tool is a GnRH stimulation test, which in the case of FHA shows a positive response of the gonadotropins to exogenous GnRH. This test easily distinguishes hypothalamic dysfunction from pituitary diseases, where hypogonadism is also characteristic [ 4 , 6 ]. Once the hypothalamic origin has been found, it is important to rule out genetic and organic diseases.

As a potential cause of amenorrhea of genetic origin, the following should be taken into account: Kallman syndrome characterized by anosmia, specific mutations , Prader—Willi syndrome with characteristic hyperorxia, obesity, retardation and other rare syndromes with idiopathic hypogonadotropic hypogonadism [ 3 , 6 , 9 ]. Features such as delayed puberty, primary amenorrhea and the presence of additional symptoms anosmia, mental retardation, extreme obesity, facial dysmorphia, malabsorption are suggestive of congenital diseases [ 6 , 9 ].

To rule out organic diseases of the hypothalamic area neoplasms, sarcoidosis, tuberculosis, parasitoids and other infiltrating lesions imaging evaluation might be helpful [ 6 ]. As described above, FHA results from depression of the hypothalamic—pituitary—ovarian axis. Impairment of GnRH and gonadotrophin secretion as a sequel is the key pathology in this trait, and also other pituitary hormone secretion is abnormal in FHA.

A typical feature of FHA is hypothalamic—pituitary—adrenal axis activation, related to stressing factors, and this phenomenon is believed to be one of the important pathogenetic factors in FHA patients [ 4 , 10 ]. Increased corticotropin-releasing hormone CRH secretion results in an increased secretion of adrenocorticotrophin from the pituitary and cortisol from the adrenal glands, and these phenomena are linked to a reduced GnRH drive. Elevated serum and also cerebrospinal cortisol concentrations have been reported in FHA [ 9 ].

Disturbances in the hypothalamic—pituitary—thyroid axis in FHA patients are also observed. They include a low-to-normal level of thyrotropin, an increased level of reverse triiodothyronine and a low level of triiodothyronine [ 2 ]. Other findings related to hypothalamic amenorrhea include elevated nighttime serum growth hormone levels and lower 24 h prolactin levels [ 11 ].

FHA patients are characterized by low serum insulin and insulin-like growth factor 1 IGF-1 and increased insulin sensitivity [ 10 ]. Besides this, androgen levels are known to be lower in FHA patients in comparison to healthy controls. Clinically, FHA should not be understood only as a symptom such as amenorrhea. This disorder has a more thought-provoking clinical image [ 2 — 4 ].

The final endocrinological consequence of impairment in GnRH and gonadotropin pulsatile secretion is profound hypoestrogenism. Hypoestrogenic status has a negative influence on different aspects of female health, not only in menopausal women but also in young individuals [ 2 — 4 ].

Moreover, hormonal disturbances are accompanied by metabolic disorders related to FHA causative factors, i. Particularly in young women, normoestrogenism and metabolic homeostasis have a critical significance for normal bone metabolism, the cardiovascular system and mental health.

The precise mechanisms underlying the pathophysiology of FHA are very complex and unclear. Numerous neuropeptides, neurotransmitters and neurosteroids play an important role in the physiological regulation of GnRH pulsatile secretion and there is evidence that these substances may be involved in the pathophysiology of FHA [ 12 ].

Particular attention should be paid to such substances as kisspeptin, neuropeptide Y NPY , ghrelin, leptin, corticotropin-releasing hormone CRH , b-endorphin and allopregnanolone. Kisspeptin, the product of the KiSS-1 gene and its G protein-coupled receptor GPR54, plays a master role in the puberty period and fertility [ 13 ].

Kisspeptin can directly stimulate GnRH secretion from the arcuate nucleus of the hypothalamus [ 14 ]. Kisspeptin administered in an acute way to women with FHA potently stimulates gonadotropin release [ 15 ].

Neuropeptide Y NPY acts as a regulator of energy balance, sexual behavior and circadian rhythm [ 16 ]. NPY affects the appetite center in the hypothalamus and stimulates feeding behavior [ 17 ]. NPY induces the production of GnRH if the concentrations of sex steroids, mainly estradiol, are high enough.

Meczekalski et al. The numbers of NPY and LH peaks were higher in patients with weight loss-related amenorrhea than in controls. Ghrelin is a peptide that stimulates appetite, but reduces fat utilization [ 20 ]. Additionally, ghrelin inhibits the hypothalamic—pituitary—gonadal axis and is responsible for the prolongation of amenorrhea in subjects who have regained normal weight [ 21 ]. Women with FHA are characterized by elevated ghrelin levels compared with healthy women [ 22 ].

Exercising or underweight amenorrheic patients are characterized by a significantly greater serum ghrelin elevation than those who remain with stable weight [ 23 ]. Leptin is an adipose tissue-derived hormone which plays a crucial role in the link between metabolic and hormonal signals and their impact on the reproductive axis [ 24 ].

Patients suffering from hypothalamic amenorrhea are characterized by considerably lower serum leptin concentrations compared with age-, weight- and body fat-matched eumenorrheic controls [ 25 ].

CRH plays an important role in the regulation of reproduction by modulating the hypothalamus—pituitary—adrenal axis as well as the hypothalamus—pituitary—ovary axis [ 26 ]. Increased secretion of glucocorticosteroids inhibits the release of GnRH and gonadotropins. These described mechanisms suggest a specific stress etiology of hypothalamic amenorrhea [ 27 ].

Beta-Endorphin is an endogenous neuropeptide, found in the hypothalamus and pituitary gland, playing a significant role in the etiopathophysiology of hypothalamic amenorrhea [ 28 ]. CRH may directly inhibit GnRH secretion and stimulate beta-endorphin production in the case of stress-related and exercise-related amenorrhea. These two conditions are characterized by increased opioidergic activity in stress- and exercise-related amenorrhea [ 27 ].

Allopregnanolone is a neurosteroid acting as an endogenous modulator of excitability of the CNS [ 29 ]. Patients suffering from hypothalamic amenorrhea demonstrate a considerable episodic release of allopregnanolone.

This specific pulsatile secretion is similar in frequency and amplitude to that in fertile women. However, a higher pulse amplitude of allopregnanolone is demonstrated in amenorrheic patients than in controls.

Likewise, higher plasma allopregnanolone levels are observed in amenorrheic subjects [ 30 ]. Functional hypothalamic disturbances and neuroendocrine aberrations have both short- and long-term consequences for reproductive health. Understandably, an impaired or diminished hypothalamic-pituitary—ovarian axis leads to anovulation and hypoestrogenism.

Lack of cyclical changes of estradiol and progesterone concentrations leads to abolished endometrial cyclicity and typically endometrium is in the persistent early profilerative phase.

Anovulation is directly linked to the neurohormonal and hormonal background of FHA. The final consequence is profound hypoestrogenism which determines anovulation [ 31 ]. If the disturbance appears during puberty, women present with primary amenorrhea. Secondary amenorrhea, which is more common in FHA, develops in postpubertal girls and women.

According to Hind [ 31 ], proper diagnosis and treatment of FHA are important due to the potential risk of infertility arising from chronic amenorrhea. Devoto and Aravena [ 32 ] found that in teenagers with hypothalamic dysfunction and menstrual disturbances, a deficient or bad response to clomiphene does not necessarily indicate a bad prognosis in terms of menses or fertility.

As stated before, anovulation is a characteristic feature of FHA, so those patients who suffer from this condition are unable to become spontaneously pregnant—a fact that is well established [ 33 ].

Another issue is how long lasting untreated hypothalamic amenorrhea influences reproductive health in the future. Delayed menarche, dyschronic puberty and the underdevelopment of secondary and tertiary sex characteristics are potential obstacles to reproductive health in girls affected by FHA during puberty. In adult women, the same disease can lead to atrophic changes in the urogenital mucosa and in the muscles of the uterus.

However, if a patient with FHA or with a history of FHA becomes pregnant, this pregnancy requires special care due to the increased risk of miscarriage and preterm labor [ 34 ].

Additionally, patients with FHA can present more obstetric complications such as impaired weight gain and compromised intrauterine fetal growth [ 35 ]. Shen ZQ et al. The occurrence of at least three consecutive regular cycles was seen in the majority of FHA women undertaking estrogen replacement therapy. The likelihood of recovery was affected by their BMI beforehand and by amenorrhea, but not by weight gain during therapy.

FHA exerts a negative influence on the skeletal system. It is related to a great extent to the failure to achieve peak bone mass PBM [ 33 ]. PBM is defined as the largest amount of bone tissue that a person has at any point in life [ 37 ]. Sex steroids estrogens, androgens , growth hormone GH and insulin growth-like 1 IGF1 are the main hormones which exert a positive influence on PBM formation [ 39 ].

In young women, estrogens are the critical determinants which ensure proper bone metabolism [ 40 ]. Estrogen action is performed in three directions: the activation of bone remodeling units, the suppression of bone resorption and the stimulation of bone formation [ 41 ]. Estrogens stimulate synthesis of the main growth factors such as transforming growth factor beta-TGF-beta, bone morphogenetic protein 6-BMP6 and insulin-like growth factor 1-IGF Estrogens are also responsible for 1,25 OH D3 expression receptors increase [ 42 ].

Additionally, estrogen can exert an influence on the inhibition of RANKL production the receptor activator of nuclear factor kappa B ligand and an increase of osteoprotegerin gene expression the inhibitor of osteoclasts formation. Therefore, prolonged hypoestrogenism in young women with FHA is associated with osteopenia and osteoporosis risk.

Other important factors include improper diet low calcium and vitamin D3 intake , undernutrition and also excessive exercises [ 45 ]. Excessive exercise exercise-related hypothalamic amenorrhea does not improve bone mass density BMD , but leads to osteopenia [ 46 ]. Hormonal factors responsible for a decrease of bone mass density are as follows: low serum IGF-I, insulin and high serum cortisol [ 42 ].

Generally, the degree of BMD decrease in FHA patients is less expressed than in patients with anorexia nervosa [ 47 , 48 ]. Reduction of PBM increases the risk of a decreased bone mass density during the pubertal period, as well as in the fertile and perimenopausal periods, which results in a major risk of pathological fractures [ 40 ].

Podfigurna-Stopa et al. FHA individuals had a decreased fat tissue mass and an imbalanced relationship between body weight, fat tissue mass and lean body mass. According to the International Society for Clinical Densitometry, amenorrhea related to hypoetrogenism lasting 6 months is the indication to perform a densitometry DEXA of the spinal column [ 51 ].

This has an important clinical aspect because FHA as a disorder of the hypothalamic—pituitary axis is the main entity responsible for BMD decrease in young women [ 52 ].

More attention should be paid to exercise among women. For most of the young women, exercise causes a positive effect—improving health and physical fitness. However, if the exercise energy expenditure increases more than energy intake, a variety of clinical manifestations can occur.

Such sports as ballet dancing, running, or gymnastics may lead to poor nutritional behaviors, resulting in low energy availability. Abnormally low BMD and osteoporosis in exercising women relate to premature bone loss and microarchitectural deterioration. Mainly, female athletes with amenorrhea are at increased risk for stress fractures and skeletal fragility [ 53 ].

Cardiovascular disease CVD is the leading cause of death in women in developed countries and, interestingly, proportionally more women die from CVD than men. As it is known, hypoestrogenism can interfere with the cardiovascular system function in many ways.

Coronary and peripheral vessels contain estrogen receptors that permit estradiol to play a regulatory role in vascular function. Estrogen excites the synthesis of nitric oxide NO through both genomic and nongenomic effects, leading to the augmented production of endothelial-derived NO, causing vasodilatation [ 54 ].

Estradiol exerts a positive, cardioprotective effect through its influence on the endothelial, myocardial and vascular function and metabolic parameters [ 55 ].

In contrast, hypoestrogenism can lead to endothelial dysfunction, an impaired bioactivity of nitric oxide, perturbation in autonomic function, activation of the rennin—angiotensin system and lipid profile changes [ 56 ]. These physiological and pathological phenomena are reflected in clinical studies.

Several investigators have demonstrated a correlation between FHA and endothelial dysfunction [ 57 ]. It was clearly shown that the flow-mediated dilation of the brachial artery which is a precise predictor of coronary endothelial dysfunction is impaired in women with FHA [ 51 ].

It is suggested that the decrease of endothelial NO bioavailability is caused by chronic estrogen deficiency. Rickenlund et al. Impaired cardiovascular function in hypothalamic amenorrhea is believed to be linked mainly to hypoestrogenism, but it is also aggravated by negative energy balance and metabolic disturbances. Patients with FHA are characterized by an impaired lipid profile and are at risk of glucose metabolism abnormalities. Women with exercise-related amenorrhea present higher serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride concentrations than healthy individuals [ 61 , 62 ].

On the other hand, premenopausal women with hypoestroegism of hypothalamic origin present an increased frequency of diabetes mellitus. Moreover, Ahmed et al. These observations substantiate the importance of cyclic ovarian function as an indicator of cardiovascular health.

However, the influence of hypoestrogenism in young women of hypothalamic origin on cardiovascular health requires further studies.

Especially the issue of the long-term consequences of FHA on CVD risk needs to be cleared to possibly minimize the risk of cardiovascular events in this group of women.

Mood in women in its essential part is linked to serum sex steroid levels, particularly estrogen [ 64 ].

Hypoestrogenism in young women with FHA is strongly related to changes in different neuropeptides, neurotransmitters and neurosteroids activity at the brain level. Specifically, serotonin, dopamine and allopregnanolone fluctuations can modulate mood in amenorrheic women [ 65 ].

The number of studies concerning this subject is very limited. FHA patients present a specific psychological profile. Gilles and Berga [ 66 ] assessed the association of cognitive function and emotional and psychiatric history in women with functional hypothalamic amenorrhea compared with amenorrheic and eumenorrheic controls.

Women with FHA endorsed more dysfunctional attitudes, had greater difficulty in coping with daily stresses and tended to endorse greater interpersonal dependence than eumenorrheic women. Hypercortisolemia is one of the characteristic hormonal features of FHA patients. Serum cortisol levels positively correlate with the Hamilton Rating Scale for Depression and Anxiety, and hypercortisolemia can be regarded as a possible mediator of mood disturbances [ 67 ].

FHA patients present a particular susceptibility to common life events, restrictive disordered eating, depressive traits and psychosomatic disorders [ 68 ]. Bomba et al. These include maturity issues, social insecurity and introversion, a tendency to depression, excessive concerns with dieting and the fear of gaining weight.

Sexual functioning is also of important significance for FHA patients. Dundon et al. Theoretically, this functioning is determined by the psychological and hormonal background. Psychological problems are aggravated by the fact that FHA is associated with anxiety, depressive symptoms and high rates of mood disorders [ 71 ].

The mediating effects of anxiety and depression may explain the occurrence of sexual dysfunction which is potentially associated with FHA. Although they were significantly higher in FHA subjects, out of the two, only depression offered a plausible explanation for sexual difficulties FHA subjects typically face. Due to the objective difficulties of correlating hormonal measurements with psychometric data, it remains uncertain whether such an association can result from a common neuroendocrine background.

Furthermore, it cannot be stated that anxiety and not depression influences sexual function differently in FHA subjects [ 72 ]. The hormonal background of sexual dysfunction in FHA may be related to profound hypoestrogenism and hypoandrogenemia [ 72 , 73 ]. It can be related to genital tract status and sexual drive.

FHA is an underestimated clinical problem. It is related to profound impairment of reproductive functions including anovulation and infertility. Patients manifest a decrease of bone mass density, which is related to an increase of fracture risk. FHA patients should be carefully diagnosed and properly managed to prevent both short- and particularly long-term medical consequences. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited.

National Center for Biotechnology Information , U. Journal of Endocrinological Investigation. FHA is a form of the defence of organism in situations where life functions are more important than reproductive function. FHA is reversible; it can be normalized after ceasing the stress situation. There are three types of FHA: weight loss related, stress-related, and exercise-related amenorrhea.

The final consequences are complex hormonal changes manifested by profound hypoestrogenism. Additionally, these patients present mild hypercortisolemia, low serum insulin levels, low insulin-like growth factor 1 IGF-1 and low total triiodothyronine.

Women health in this disorder is disturbed in several aspects including the skeletal system, cardiovascular system, and mental problems. Patients manifest a decrease in bone mass density, which is related to an increase in fracture risk.