Blazej Meczekalski

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 β-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.

New markers of insulin resistance in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in women of reproductive age. The diagnostic criteria include two out of three features: hyperandrogenism, polycystic ovaries on ultrasound and menstrual irregularities (Rotterdam Criteria 2003). PCOS patients are more vulnerable to develop diabetes, cardiovascular diseases and metabolic syndrome. Insulin resistance (IR) is prevalent in women with PCOS independently of obesity and is critically involved in reproductive and metabolic complications of the syndrome. Several tests have been developed to measure IR, some very reliable but complex like the hyperinsulinemic euglycemic glucose clamp and others less precise but easier and less invasive like HOMA-IR. New markers are needed to reach a more reliable assessment of insulin resistance. To date, several surrogate markers have been proposed in the literature to facilitate and improve the determination of IR. Many new proteins are strongly involved with PCOS physiopathology and IR, such as some adipocytokines (adiponectin, visfatin, vaspin and apelin), copeptin, irisin, PAI-1 and zonulin. Many other proteins have been proposed as potential new markers of IR in PCOS, such as resistin, leptin, RBP4, kisspetin and ghrelin, but their role is still controversial. In this review, we provide a short characterization of these new markers, recently studied as indicators of metabolic state.

Long-term consequences of anorexia nervosa

Anorexia nervosa (AN) is a psychiatric disorder that occurs mainly in female adolescents and young women. The obsessive fear of weight gain, critically limited food intake and neuroendocrine aberrations characteristic of AN have both short- and long-term consequences for the reproductive, cardiovascular, gastrointestinal and skeletal systems. Neuroendocrine changes include impairment of gonadotropin releasing-hormone (GnRH) pulsatile secretion and changes in neuropeptide activity at the hypothalamic level, which cause profound hypoestrogenism. AN is related to a decrease in bone mass density, which can lead to osteopenia and osteoporosis and a significant increase in fracture risk in later life. Rates of birth complications and low birth weight may be higher in women with previous AN. The condition is associated with fertility problems, unplanned pregnancies and generally negative attitudes to pregnancy. During pregnancy, women with the condition have higher rates of hyperemesis gravidarum, anaemia and obstetric complications, as well as impaired weight gain and compromised intrauterine foetal growth. It is reported that 80% of AN patients are affected by a cardiac complications such as sinus bradycardia, a prolonged QT interval on electrocardiography, arrythmias, myocardial mass modification and hypotension. A decrease in bone mineral density (BMD) is one of the most important medical consequences of AN. Reduced BMD may subsequently lead to a three- to seven-fold increased risk of spontaneous fractures. Untreated AN is associated with a significant increase in the risk of death. Better detection and sophisticated therapy should prevent the long-term consequences of this disorder. The aims of treatment are not only recovery but also prophylaxis and relief of the long-term effects of this disorder. Further investigations of the long-term disease risk are needed.

Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women

OBJECTIVES The aim of this study was evaluation of the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women. METHODS The study group were 20 postmenopausal women, mean age 48.7 years (S.D. +/- 4.9 years). The control group were ten regularly menstruating women, mean age 32.6 years (S.D. +/- 13.2 years). In the studied group we measured the severity of climacteric syndrome with the use of Kupperman index and serum FSH and 17beta-estradiol level with the use of radioimmunological method. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice, the reference region was delineated in the cerebellum. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. RESULTS Before HRT mean value of the Kupperman index in the study group was 29.8 points (S.D. +/- 7.1 points); 17beta-estradiol 27 pg/ml (S.D. +/- 2 pg/ml); FSH 56 IU/l (S.D. +/- 49.5 IU/l); SPECT study revealed cerebral blood flow impairment in ten women. In all the studied slices cerebral blood flow was lower in the study group than in the controls. After 12 months of HRT the mean value of the Kupperman index in the study group was 13.2 points (S.D. +/- 2.1 points) (P < 0.05); 17beta-estradiol 44 pg/ml (S.D. +/- 25 pg/ml); FSH 36.4 IU/l (S.D. +/- 57.3 ng/ml); we found cerebral blood flow increase in all studied slices: right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%* (* P < 0.05). CONCLUSIONS Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17beta-estradiol level.

Functional hypothalamic amenorrhea and its influence on women's health.

IntroductionFunctional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea. There are three types of FHA: weight loss-related, stress-related, and exercise-related amenorrhea. FHA results from the aberrations in pulsatile gonadotropin-releasing hormone (GnRH) secretion, which in turn causes impairment of the gonadotropins (follicle-stimulating hormone and luteinizing hormone). 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.AimThe aim of this work is to review the available data concerning the effects of FHA on different aspects of women’s health.ResultsFunctional hypothalamic amenorrhea is related to profound impairment of reproductive functions including anovulation and infertility. Women’s 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. 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.ConclusionsFHA patients should be carefully diagnosed and properly managed to prevent both short- and long-term medical consequences.

Polymorphic variants of genes encoding MTHFR, MTR, and MTHFD1 and the risk of depression in postmenopausal women in Poland

OBJECTIVE Disturbances in the folate-dependent one-carbon metabolism have been reported in depression. Polymorphic variants of genes encoding key enzymes of folate and methionine metabolism may have an impact on catecholamine catabolism conducted by catechol-O-methyltransferase. METHODS The distribution of polymorphisms of genes encoding methylenetetrahydrofolate reductase (MTHFR); methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1) was examined in postmenopausal women with (n=83) and without depression (n=89). RESULTS We found a significant contribution of the MTHFR 677C>T polymorphic variants to depression in postmenopausal women. Odds ratio (OR) for women with depression and MTHFR TT genotype was 3.478 (95% CI=1.377-8.783), P=0.0096 and OR of the TT and CT genotypes was 2.345 (95% CI=1.258-4.373), P=0.0086. Moreover, after stratification based on depression severity in postmenopausal women, we found that the MTHFR TT genotype displayed a 4.831-fold increased risk of moderate and severe depression (95% CI=1.975-11.820, P=0.0008). We did not observe statistical differences in the distribution of MTR 2756A>G and MTHFD1 1958G>A polymorphic variants in groups of postmenopausal women with and without depression. However, the MTR GG genotype exhibited a 5.750-fold increased risk of moderate and severe depression in postmenopausal women (95% CI=1.547-21.379, P=0.013). CONCLUSIONS Our findings indicate a significant role of folate and possible methionine metabolism involvement in the development of depression in postmenopausal women.

Pregnancy complications in polycystic ovary syndrome patients.

Abstract Infertility is a widely disputed problem affecting patients suffering from polycystic ovary syndrome (PCOS). As a serious dysfunction, it frequently occurs in PCOS patients. It is, therefore, important to devote more attention to pregnancy in PCOS sufferers. According to various data, the risk of miscarriage in PCOS women is three times higher than the risk of miscarriage in healthy women. Unfortunately, the risk of most frequent pregnancy pathologies is also higher for PCOS patients, as gestational diabetes (GD), pregnancy-induced hypertension and pre-eclampsia, and small for gestational age (SGA) children. Impaired glucose tolerance and GD in pregnant PCOS patients occur more frequently than in healthy women. A quadruple increase in the risk of pregnancy-induced hypertension linked to arterial wall stiffness has also been observed in PCOS patients. The risk of pre-eclampsia, the most severe of all complications, is also four times higher in those suffering from PCOS. Pre-eclampsia is also more frequent in patients presenting additional risk factors accompanying PCOS, such as obesity or GD. At that point, it should be mentioned that PCOS patients are under 2.5 higher risk of giving birth to SGA children than healthy women. It appears that SGA can be linked to insulin resistance and insulin-dependent growth dysfunction. Therefore, PCOS pregnant women are patients of special obstetrical care.

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

Context: 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/cm2), lumbar spine (L2–L4) bone mineral density (SBMD; g/cm2), 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.

Fertility in women of late reproductive age: the role of serum anti-Müllerian hormone (AMH) levels in its assessment.

IntroductionFertility is referred to the capability for having offspring and can be evaluated by fertility rate. Women’s fertility is strictly dependent on individual’s age. The fertility peak occurs in the early 20s, and it starts to decline in the third and fourth decades of life (falling sharply after age 35).AimThe aim of this work is to review the available data concerning fertility in women of late reproductive age, especially the role of serum anti-Müllerian hormone (AMH) levels.Results There are a lot of factors responsible for decrease of fertility in women of late reproductive age. These factors can be classified as oocyte-dependent (decrease in oocyte quantity and quality) and oocyte-independent (reproductive organs [uterus, oviducts] status and general health). Anti-Müllerian hormone (AMH) is a dimeric glycoprotein of the transforming growth factor-β (TGF-β) superfamily produced directly by the ovarian granulosa cells of secondary, preantral, and early antral follicles. It has been used as an ovarian reserve marker since 2002. Anti-Müllerian hormone seems to be the best endocrine marker for assessing the age-related decline of the ovarian pool in healthy women. Evaluation of AMH’s predictive value in the naturally aging population is important for counseling women about reproductive planning as well as for treatment planning for women experiencing hormone-sensitive gynecological conditions such as endometriosis and fibroids.Conclusions AMH can be considered as an indicator of fertility in late reproductive age women and pregnancy outcome in assisted reproductive technology cycles. AMH can strongly predict poor response in the controlled ovarian stimulation.

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.