Serum Levels of Tryptophan, 5-Hydroxytryptophan and Serotonin in Patients Affected with Different Forms of Amenorrhea

Tryptophan (Trp) is present in the serum, partly bound to albumine and in the free form. The unbound portion of circulating tryptophan has the property of crossing the hematoencephalic barrier and being converted within the brain into serotonin (5-HT) through the enzymatic processes of hydroxylation and decarboxylation. The serotoninergic system plays an important role in neuroendocrine control of reproductive hormone secretion, and in particular, it may influence GnRH pulsatility, a function essential for reproductive processes. In this study, we analysed serum levels of tryptophan, serotonin and 5-hydroxytryptophan (5-HTP) in women with three different forms of amenorrhea: 16 patients were diagnosed with anorexia nervosa, 60 patients with functional hypothalamic amenorrhea, and 14 patients with hyperprolactinemia. Data were compared with those of a group of 25 healthy women. Serum Trp levels were significantly (P ≤ 0.05) lower in the anorexic (11.64 ± 0.53 μg/ml, mean ± S.E.) than in the control (12.98 ± 0.37 μg/ml) groups. In addition, in the anorexic group a statistical dispersion of Trp values was shown indicating a bimodal data distribution suggesting the existence of two different subgroups of patients. Regarding 5-HTP, an increase of its serum level was observed in all the groups with amenorrhea with the highest value in hyperprolactinemic patients. On the contrary, no statistical differences in serum 5-HT levels among the four analyzed groups were observed

Why kisspeptin is such important for reproduction?

Recently discovered neuropeptide called kisspeptin is thought to be an essential gatekeeper in control of reproduction. Kisspeptin, the product of KiSS-1 gene and its G protein-coupled receptor GPR54 play a master role in the puberty period and fertility. This 54 amino acid peptide known also as metastatin, because of its metastasis suppression ability is also implicated in tumour biology. Kisspeptin/GPR54 system activates the hypothalamus-pituitary-ovarian axis. Its mechanism is not clearly understood. Kisspeptin influence is found above more at the level of hypothalamus but also at the pituitary and ovaries level. Kisspeptin can directly stimulate GnRH secretion from arcuate nucleus of hypothalamus. It is thought that kisspeptin plays an essential role in the metabolic regulation of fertility. In negative energy balance conditions an expression of KiSS-1 gene is decreased. Inactivating GPR54 mutations cause hypogonadotropic hypogonadism in humans. Simultaneously, mutations which increase GPR54 signalling are connected with gonadotropin-dependent premature puberty. Lately, possible therapeutic role of kisspeptin administration has been discussed. It was stated that kisspeptin might be used to manipulate the hypothalamic-pituitary-gonadal axis in humans. However, further studies are essential to reveal the exact mechanism and role of GPR54 agonists and antagonists applications. Moreover, the role of kisspeptin in the aspect of detection and treatment of specific cancers should be discovered

Hypoestrogenism in young women and its influence on bone mass density

One of the most important hormonal factors responsible for bone health is estradiol. Genetic factors, adequacy of hormonal functioning, nutrition and physical activity may be the markers of bone status and development in young women. During adolescence, women reach peak bone acquisition and develop a skeletal mass. This process is largely regulated by endocrine factors mainly such as adequate levels of gonadal, adrenal and pituitary hormones. The crucial role played by estradiol and its impact on bones are very multiple. Estradiol induces growth factors' activation, receptor activator of nuclear factor kappa B ligand (RANKL) production inhibition and is mainly referred to antiresorptive activity. Clinical situations leading to hypoestrogenism has been linked to decreased bone mineral density leading to osteopenia and osteoporosis. This status both in fertile and perimenopausal women can increase the risk of pathological fractures. Such conditions as hypothalamic-pituitary insufficiency (functional hypothalamic amenorrhea, anorexia nervosa, Kallmann syndrome, hyperprolactinemia), ovarian failure (gonadal dysgenesis, premature ovarian failure) and iatrogenic treatment (surgery, chemotherapy, radiotherapy) can cause hypoestrogenism. The treatment of osteopenia and osteoporosis caused by hypoestrogenism is very essential and multidirectional. The crucial role of the therapy is the achievement of proper serum estradiol concentration and eliminate the causes of hypoestrogenism

Kisspeptin and LH pulsatile temporal coupling in PCOS patients

Purpose: To evaluate the temporal coupling between spontaneous kisspeptin and luteinizing hormone (LH) pulsatile releases in polycystic ovary syndrome (PCOS) patients. Methods: We examined 71 patients diagnosed with PCOS. A 2 h pulsatility study was performed to evaluate serum kisspeptin and LH pulse frequency and concentration, sampled every 10 min; baseline follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), cortisol, 17-hydroksy-progesterone (17OHP), testosterone (T), free testosterone index (FTI, and insulin levels were also measured. Detect and Specific Concordance (SC) algorithms were used to evaluate the temporal coupling associations between spontaneous episodic secretion of kisspeptin and LH. Results: All PCOS patients demonstrated LH and kisspeptin pulsatile secretions. When the SC index was calculated across the sample of PCOS patients (n = 71), no temporal coupling was observed between kisspeptin and LH pulses. When PCOS patients were subdivided according to their menstrual cyclicity, oligomenorrheic patients demonstrated elevated kisspeptin pulse frequency. Additionally, the SC index reveled a temporal coupling between kisspeptin and LH secretory peaks only in eumenorrheic patients (n = 30, intermenstrual interval < 45 days). Oligomenorrheic PCOS patients (intermenstrual interval > 45 days) did not demonstrate temporal coupling between kisspeptin and LH secretory peaks. Conclusions: The study of the endogenous kisspeptin and LH pulsatile release revealed the temporal coupling of kisspeptin with LH secretory pulses only in eumenorrheic. This data supports the hypothesis that neuroendocrine impairments in PCOS affect the coupling of kisspeptin with LH pulses and potentially worsen as the disease progresses, becoming unequivocally evident in oligomenorrheic PCOS patients

Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations

Functional hypothalamic amenorrhea (FHA) is defined as a non-organic and reversible disorder in which the impairment of gonadotropin-releasing hormone (GnRH) pulsatile secretion plays a key role. There are main three types of FHA: stress-related amenorrhea, weight loss-related amenorrhea and exercise-related amenorrhea. The spectrum of GnRH-luteinizing hormone (LH) disturbances in FHA is very broad and includes lower mean frequency of LH pulses, complete absence of LH pulsatility, normal-appearing secretion pattern and higher mean frequency of LH pulses. Precise mechanisms underlying the pathophysiology of FHA are very complex and unclear. Numerous neuropeptides, neurotransmitters and neurosteroids play important roles in the physiological regulation of GnRH pulsatile secretion and there is evidence that different neuropeptides may be involved in the pathophysiology of FHA. Particular attention is paid to such substances as allopregnanolone, neuropeptide Y, corticotropin-releasing hormone, leptin, ghrelin and beta-endorphin. Some studies reveal significant changes in these mentioned substances in patients with FHA. There are also speculations about use some of these substances or their antagonists in the treatment of FHA

Skeletal status and body composition in young women with functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) related to hypoestrogenism and hormonal status may influence skeletal homeostasis and body composition. The study aimed to evaluate hormones concentrations, body composition and bone strength in FHA cases. PATIENTS AND METHODS: Total body scans using DXA method (DPX-L, GE Lunar) were performed in a group of 27 women aged 21.8 years ± 3.9 with FHA related to weight loss. References of healthy control subjects were used to calculate Z-scores (age and gender matched), SD-scores (height and gender matched), and SDs-scores (weight and gender matched). Whole skeleton bone mineral content (TBBMC, g) and density (TBBMD, g/cm(2)), lumbar spine (L2-L4) bone mineral density (SBMD; g/cm(2)), lean body mass (LBM, g) and fat mass (FM, g) were investigated. Relative bone strength index was calculated as the TBBMC/LBM ratio. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, and prolactin (PRL) concentrations were assayed to characterize hormonal profile of FHA cases. RESULTS: Hormonal evaluation in patients with FHA revealed significantly decreased serum concentrations of gonadotropins and estradiol. Serum LH concentrations were 1.47 ± 0.89 mIU/ml, FSH 4.44 ± 1.94 mIU/ml. Estradiol concentrations in serum were 27.08 ± 13.10 pg/ml. As evidenced by Z-scores, FHA cases had decreased SBMD, TBBMD and TBBMC Z-scores of -1.23 ± 0.90 (p < 0.0001), -0.72 ± 0.86 (p < 0.001), and -0.90 ± 1.40 (p < 0.01), respectively. Reduced FM, LBM and FM/LBM ratio Z-scores of -1.80 ± 2.28 (p < 0.001), -0.59 ± 1.49 (p < 0.05) and -0.74 ± 1.55 (p < 0.05), but not TBBMC/LBM Z-score of -0.54 ± 2.14 (ns) were noted in FHA cases compared with healthy control cases. TBBMC, TBBMD, TBBMC/LBM when BH- or BW-matched were normal as evidenced by SD-scores and SDs-scores. SBMD remained reduced when BH-matched (SD-score = -0.40 ± 0.86; p < 0.05) whereas FM and FM/LBM were lower than expected in healthy, both compared to BH- and BW-dependent references. The length of amenorrhea in months negatively correlated with SBMD Z-score (R = -0.39, p < 0.05), and SD-scores for SBMD (R = -0.48), TBBMD (R = -0.43), TBBMC (R = -0.46) (all p < 0.05) and positively with SDs-scores for FM (R = 0.44, p < 0.05). CONCLUSION: Patients with FHA were characterized by lower concentrations of serum FSH, LH and estradiol concentrations. Moreover, FHA cases had decreased FM and an imbalanced relationship between BW, FM, and LBM. Despite reduced BMD and BMC, bone strength was not significantly affected by FHA

Kisspeptin and LH pulsatility in patients with functional hypothalamic amenorrhea

Purpose: Functional hypothalamic amenorrhea (FHA) occurs in response to exaggerated stressors with or without body weight loss. Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH and kisspeptin is one of them. Our study aimed to evaluate the putative temporal coupling between kisspeptin and GnRH-induced LH pulsatile secretion. Methods: In total, 71 patients with FHA were selected for this study. All patients undergo to a pulsatility study for LH and kisspeptin evaluation (120 min, sampling every 10 min), and to an endocrine evaluation for prolactin (PRL), estradiol (E2), androstenedione (A), 17-hydroxy-progesterone (17OHP), TSH, fT3, fT4, insulin, cortisol and testosterone (T), glucose, total cholesterol, triglycerides. Results: Our data demonstrated kisspeptin and LH pulsatile secretions and that both hormones are co-secreted and temporally coupled at time 0 (p &lt; 0.05). When patients were subdivided in hypo-LH (≤3 mIU/ml, n = 58) and normo-LH (&gt;3 mIU/ml, n = 13), more insights were observed on the specific correlations of metabolic and hormone profiles with pulsatility indexes of LH and kisspeptin. Conclusions: Our study demonstrated the presence of a distinct kisspeptin episodic secretion in patients with FHA, and showed the temporally coupling of kisspeptin with LH secretory episodes thus supporting that though in amenorrhea, the reproductive axis is still relying on kisspeptin to drive GnRH discharge. In addition, correlations among hormonal data sustain the hypothesis that stress-induced compensatory events are the main direct and indirect promoters of the reproductive blockade in patients affected by FHA

The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications

Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65–75% of symptoms connected with postmenopausal period are vasomotor symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS