Agnieszka Podfigurna

The role of progesterone therapy in early pregnancy: from physiological role to therapeutic utility

Abstract Progesterone is a steroid hormone of essential role in reproduction. In early pregnancy, it is responsible for preparation of endometrium for implantation process and maintenance of gestational sac in uterus, also by modulation of maternal immune system. Even though, several indices has been proposed as markers of endogenous progesterone synthesis (progesterone or luteinizing hormone measurements, endometrial biopsy), none has been proved to be reliable in detecting luteal phase defect. Currently, several pharmaceutical formulations are available, but in clinical setting the non-oral formulations seems to be effective in therapy. Progesterone is effective in the treatment of patients undergoing assisted reproductive technology procedure, as a luteal phase support. Some studies showed also its efficacy in the treatment of threatening or recurrent miscarriage, but newer trials neglected this beneficial effect. Due to controversies regarding utility of progesterone supplementation in these conditions, further studies are needed to address this issue.

Kisspeptin and LH pulsatile temporal coupling in PCOS patients

PurposeTo evaluate the temporal coupling between spontaneous kisspeptin and luteinizing hormone (LH) pulsatile releases in polycystic ovary syndrome (PCOS) patients.MethodsWe 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.ResultsAll 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.ConclusionsThe 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.

Age-related decline in AMH is assay dependent limiting clinical interpretation of repeat AMH measures across the reproductive lifespan

Abstract Purpose: The aim of the study was to determine whether the assays exhibit an interaction with age and exhibit heterogeneous age related declines in AMH. Apart of chronological age, AMH variation was investigated with relation to menstrual cycle day (MCD). The goal implicates two questions: Are distributions of AMH concentrations homogenous after adjustment for the specific AMH assay? Does age-assay product has an effect on AMH depletion? Methods: The study was conducted by examining results of AMH tests performed for 12,917 women with four types of AMH assays: Immunotech I generation kit (IMI, 4016 samples), Beckman Coulter II generation kit RUO (BCII RUO, 3430 samples), Beckman Coulter II generation kit with IVD certificate (BCII IVD, 830 samples), and Ansh Labs I generation kit (AnshLabs, 4641 samples). Statistical analysis included ACNOVA and least square regression technique. Results: Menstrual cycle day has no effect on AMH measurements. On the other hand, AMH values differed substantially between the four assays, with a marked discordance in the rate of age-related AMH decline for the four assays (ranging from –8.16% (95% CI: –8.79, –7.54) to –11.53% (95% CI –12.20, –10.87), with a significant interaction between age and assay. Conclusions: (1) The distribution of AMH concentration is heterogeneous after controlling the age across assays; (2) the rate of AMH decline as a function of age is different for the four manual AMH ELISA assays.

Modulatory effects of l-carnitine plus l-acetyl-carnitine on neuroendocrine control of hypothalamic functions in functional hypothalamic amenorrhea (FHA)

Abstract Functional hypothalamic amenorrhea (FHA) is a relatively frequent disease due to the combination of metabolic, physical, or psychological stressors. It is characterized by the low endogenous GnRH-induced gonadotropin secretion, thus triggering the ovarian blockade and a hypoestrogenic condition. Up to now various therapeutical strategies have been proposed, both using hormonal treatment as well as neuroactive compounds. Since carnitine, namely l-acetyl-carnitine (LAC), has been demonstrated to be effective in the modulation of the central hypothalamic control of GnRH secretion, we aimed to evaluate whether a combined integrative treatment for 12 weeks of LAC (250 mg/die) and l-carnitine (500 mg/die) was effective in improving the endocrine and metabolic pathways in a group of patients (n = 27) with FHA. After the treatment, interval mean LH plasma levels increased while those of cortisol and amylase decreased significantly. When patients were subdivided according to baseline LH levels, only hypo-LH patients showed the significant increase of LH plasma levels and the significant decrease of both cortisol and amylase plasma levels. The increased 17OHP/cortisol ratio, as index of the adrenal activity, demonstrated the reduced stress-induced adrenal activity. In conclusion, our data sustain the hypothesis that the integrative administration of LAC plus l-carnitine reduced both the metabolic and the neuroendocrine impairment of patients with FHA.

Reproduction in premature ovarian insufficiency patients – from latest studies to therapeutic approach

Normal function of the ovaries, which is responsible for the hormonal and reproductive processes, is one of the most important determinants of fertility. Premature ovarian insufficiency (POI) is defined as cessation of menstrual cycle, increased serum follicle-stimulating hormone (FSH) levels, and decrease serum oestradiol levels in women before the age of 40 years. POI concerns about 1% of women and is characterised by severely diminished fertility. For the POI patient, this is one of the most dramatic problems. It influences their psychological status and functioning in society. The chance for spontaneous conception is very limited and ranges from 4 to 8%. For contemporary medicine, infertility treatment in POI patients is a challenge. The problem is that there are no effective therapies to augment ovarian activity in POI patients. At present, oocyte donation is regarded as the only proven method in the treatment of infertility in POI patients. However, nowadays we can observe important progress in the development of fertility preservation methods. In the POI field it refers to cryopreservation of oocytes, embryos, and ovarian tissue. Additionally, new methods known as in vitro activation of dormant follicles and possible use of stem cells should be mentioned.

Cardiovascular health in patients with premature ovarian insufficiency. Management of long-term consequences

Cardiovascular diseases (CVDs) represent the world’s leading cause of death among women. Women with premature ovarian insufficiency (POI) may be at higher risk of cardiovascular disease, such as myocardial infarction or stroke, than women with normal menopause. The increased burden may be mediated by a worsening of cardiovascular risk factors, such as lipid profiles, with accompanying loss of ovarian function. In contrast, the increased burden may be caused by factors that precede and potentially contribute to both CVD events and ovarian decline, such as smoking. Women with X chromosome-related POI like Turner syndrome (TS) are a distinct group with unique medical needs. Regardless of the cause, women with POI may serve as an important population to target for CVD screening and prevention strategies. These strategies should include the use of CVD risk stratification tools to identify women who may benefit from lifestyle modification and pharmacological therapy to prevent CVD.

Metabolic Profile of Patients with Premature Ovarian Insufficiency

Premature ovarian insufficiency (POI) is hypogonadism associated with amenorrhea, increased levels of gonadotropins, and hypoestrogenism. Deficiency of estrogens may contribute to higher risk of cardiovascular diseases and death. POI patients present several risk factors for the development of cardiovascular diseases (CVD): endothelial dysfunction, abnormal lipid profile, insulin resistance, and insulin action disturbances. Therefore, patients present a higher risk of developing metabolic syndrome. Materials and methods: Follicle stimulating hormone (FSH), luteinizing hormone (LH), 17β-estradiol (E2), prolactin (PRL), testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), thyroid stimulating hormone (TSH), thyroxine (fT4), fasting serum glucose and insulin concentrations, homeostatic model for insulin resistance (HOMA-IR), and lipid profiles were assessed in 56 women (mean age: 30.7 ± 6.9) suffering from POI diagnosed according to European Society of Human Reproduction and Embryology (ESHRE) criteria and 68 healthy age-and-weight matched women (mean age: 27.3 ± 4.5). Results: After regression analysis with BMI and age correction, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) serum concentrations were found to be significantly higher in the POI group, when compared to healthy subjects, whilst triglycerides, glucose, insulin serum concentrations, HOMA-IR, as well as systolic (SBP) and diastolic blood pressure (DBP) did not differ significantly between both groups. A significant positive correlation was identified between TC and LDL-C levels, regardless of BMI and age, whilst SBP correlated only with serum glucose concentration. Additionally, FSH correlated positively with fasting serum glucose concentration after BMI and age correction. Conclusions: Certain metabolic parameters appeared to correlate with POI and these correlations persisted after correction for BMI and age. More research is required to determine the influence of absent ovulatory function on metabolic profiles in POI women. This information may additionally help in early identification of CVD risk factors in those patients.

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

Abstract 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. 摘要 围绝经期的妇女会出现一系列症状, 这些症状会干扰身体, 性生活和社交。绝经期间约65-75％的症状是血管舒缩症状（VMS）, 如潮热和盗汗。潮热是与皮肤血管舒张和核心温度下降相关的主观热感。VMS被怀疑与促性腺激素释放激素（GnRH）脉冲式释放过多和随后的黄体生成素（LH）分泌密切相关。同时研究显示, 卵巢中合成的类固醇激素缺乏负反馈导致位于漏斗核中的肥大Kisspeptin /神经激肽B /强啡肽（KNDy）神经元过度活化。 Kisspeptin（KISS1）和神经激肽B（NKB）的过度分泌以及强啡肽的下调在GnRH脉冲的产生中起主导作用, 反之导致VMS的发生。给予NK3受体特异性激动剂, 高效选择性NK3R激动剂导致绝经后妇女血清LH浓度增加, 诱导VMS发生, 心率增加和皮肤温度升高。这些发现表明, 对KNDy神经元的调节可能成为治疗VMS的新方法。

Testing ovarian reserve in pre-menopausal women: why, whom and how?

Numerous social and environmental factors (environmental hazards, social factors such as education and career, higher economic status desired before the decision is made to have children) influence a womens decision to postpone pregnancy until late reproductive age. In turn, age is related to a fall in ovarian reserve. The main goal of testing ovarian reserve is the identification of women with so-called diminished ovarian reserve (DOR). Additionally, it provides assistance in the counselling of women who are planning to use assisted reproductive techniques (ART). This review examines current methods of testing ovarian reserve and their application. The most useful methods of assessing ovarian reserve are ultrasonographic count of ovarian antral follicles (AFC) and serum tests of both the anti-Müllerian hormone (AMH) level and the third-day level of follicle stimulating hormone (FSH). However, there are limitations to the currently used methods of testing ovarian reserve, especially in relation to their specificity and sensitivity. It is also difficult to predict egg quality based on these tests. The value of screening programmes of ovarian reserve is yet to be determined.

Brain-derived neurotrophic factor (BDNF) plasma concentration in patients diagnosed with premature ovarian insufficiency (POI)

Abstract Premature ovarian insufficiency (POI) is defined as a cessation of function of ovaries in women younger than 40 years old. Brain-derived neurotrophic factor (BDNF) is a protein critically involved in neuronal growth and metabolism. BDNF also has been shown to be important regulator of oocyte maturation. Recent data show that BDNF can be potentially involved in POI pathology. The aim of the study was to assess the BDNF plasma concentrations in patients diagnosed with idiopathic POI. 23 women diagnosed with POI (age 31 ± 7 years) and 18 (age 31 ± 3) controls were included to the study, matched according to age and body mass index. The BDNF concentrations were measured using competitive enzyme-linked immunosorbent assay (ELISA). Hormonal and metabolic parameters were measured in all individuals, in controls in late follicular phase. The POI group demonstrated lower mean plasma concentrations of BDNF (429.25 ± 65.52 pg/ml) in comparison to healthy controls (479.75 ± 34.75 pg/ml, p = 0.0345). The BDNF plasma concentration correlated negatively (R = −0.79, p < 0.001) with number of months since last menstrual period. There was a positive correlation between BDNF and progesterone in controls. In conclusion, POI patients show significantly lower BDNF plasma concentration and it correlates with the duration of amenorrhea. This observation brings important potential insights to the pathology of POI.