The analysis of polymorphism in the genes for the receptors of sex steroids in women with the premature ovarian failure

Prosečna starost za ulazak u menopauzu u populacijama žena zapadnih zemalja je približno 51 godina. Prevremenu disfunkciju ovarijuma (POI) karakteriše amenoreja, hipoestrogenizam i povišeni gonadotropini kod žena mlađih od 40 godina. Uzroci POI su heterogeni, uključujući aberacije X hromozoma, infekcije, jatrogene uzroke (hirurgija, hemoterapija, zračenje) i autoimmune bolesti. Oko 20-30% žena sa POI ima i porodičnu anamnezu, sa ženskim članovima porodice koji nose istu dijagnozu. Stoga je genetska osnova za poremećaj verovatno uzrok ovog kliničkog stanja. Poznato je da normalni razvoj i funkcija jajnika zahtevaju ekspresiju i pravilnu koordinaciju mnogih gena. Navedeni mehanizmi su većinom nepoznati i uprkos genetskim defektima koji su identifikovani u nekoliko gena kandidata, u velikom broju POI slučajeva nije pronađen nijedan uzrok i zato su klasifikovani kao idiopatski POI. S obzirom da su veličina inicijalne folikularne formacije i brzina folikularnog trošenja povezane sa starošću pri menopauzi i s obzirom na činjenicu da ovi zametci ćelija izražavaju gonado steroidne receptore u različitim fazama razvoja, moguće je da genetičke varijante u genima za receptore polnih steroida, koje su uključene u održavanje funkcije jajnika, mogu uticati na rizik od PPOI. Osnovni modulatori folikulogeneze su estrogenski receptori (ERα i ERβ) koji direktno kroz regulisanje hipofiza-gonadne ose omogućavaju delovanje estrogena. Sekventni polimorfizam ERα gena (ESR1:estrogen receptor 1) je pokazao povezanost sa osteoporozom, neobjašnjivom neplodnošću, nižim odgovorom na stimulaciju jajnika, fibromima u materici i endometriozom. Nedavna istraživanja su pokazala da su mikrosatelitni polimorfizmi gena za ESR1 povezani sa PPOI u korejskoj kohorti. Nedostatak estrogena povezan je sa povećanim poremećajem kostiju, ubrzanim gubitkom kostane mase što dovodi do povećane podložnosti osteoporozi i frakturi kostiju. Nasleđivanje koštane mase je pod poligenskom kontrolom. SOHLH1 i SOHLH2 geni su faktori transkripcije vazni za razvoj PPOI. SOHLH2 gen nalazi se na 13 hromozomu, i jedan je od testis-specifičnih faktora koji su od suštinske važnosti za spermatogenezu, ovogenezu i folikulogenezu. SOHLH 1 i 2 geni su izraženi isključivo u primordijalnim folikulima do primarne folikularne faze i predstavljaju master regulatore gena jajne ćelije odgovorne za rani rast i diferencijaciju folikula...The average age for menopause in Western populations is approximately 51 year. Premature ovarian failure (PPOI) is characterised by amenorrhoea, hypoestrogenism and elevated gonadotropins and affects of women under the age of 40. The causes of PPOI are heterogeneous, including chromosome X defects, infections, iatrogenic (surgery, chemotherapy, radiation), and autoimmune disease. Approximately 20-30% of women with PPOI will have other affected female members, hence a genetic basis for the disorder is a likely cause for this clinical scenario. It is known that normal ovarian development and function require the expression and proper coordination of many genes. The underlying mechanisms are largely unknown and despite the genetic defects identified in several candidate genes, in a large proportion of PPOI cases no cause has been found; and hence they are classified as idiopathic PPOI. Considering that initial follicular pool size and the rate of follicular depletion are associated with the age of menopause and given the fact that these germ cells express gonadal steroid receptors at various stages of development, it is plausible that genetic variants in sex hormone receptor genes involved in maintaining ovarian function could affect the risk of PPOI. Estrogen actions mediated through its cognate receptors (ERα and ERβ) are essential modulators of folliculogenesis, directly throught regulation of the hypophyseal-gonadas axis. Sequence polymorphisms of the ERα gene (ESR1: estrogen receptor 1) have been shown to be associated with osteoporosis, unexplained infertility and lower response to ovarian hyperstimulation, and uterine fibroids and endometriosis. A recent study reports that ESR1 gene polymorphisms are associated with PPOI in Korean cohort. Deficiency of estrogen, a critical reproductive hormone for bone acquisition, is associated with an increased bone turnover and accelerated bone loss, leading to the increased susceptibility to osteoporosis and bone fractures. The inheritance of bone mass is under polygenic control.SOHLH 1 and 2 are transcription factors involved in etiology ofPPOI.SOHLH2 gene is situated on chromosome 13 and is testis-specific factor important for spermatogenesis, oogenesis and folliculogenesis. Both, SOHLH 1 and 2,are expressed exclusively in primordial follicles up until the primary follicle stage, and are master regulators of oocyte-specific genes critical for early follicle growth and differentiation..

Uloga omjera E2/P u etiologiji fibrocistične bolesti dojke, mastalgije i mastodinije

The aim of the study was to assess the role of the estradiol and progesterone relationship during the late luteal phase and the occurrence of fibrocystic breast disease (FBD). The concentration of estradiol/progesterone was measured in the group of women with FBD as study group (n=50) and control group of women without FBD (n=40). All women had regular ovulation cycles. Blood samples for estradiol (E2), progesterone (P) and prolactin determination were obtained in the morning at 8 am on days 21 and 24 of menstrual cycle. Significant mastalgia and mastodynia history in women with FBD was obtained with yes or no questionnaire. FBD diagnosis was confirmed with ultrasound (size and number of simple cysts). In the control group, a reduced E2/P ratio was noticed from day 21 to day 24 of the cycle (from 14.8±11.5 pg/mL to 9.1±6.1 pg/mL; p<0.05), which was not recorded in the group of women with FBD (study group). Even the slightest disturbance of the E2/P ratio may contribute to the occurrence of FBD with clinical manifestations of mastalgia and mastodynia.Namjera rada je bila ispitati ulogu odnosa estradiola i progesterona za vrijeme lutealne faze ciklusa u pojavljivanju fibrocistične bolesti dojke (FBD). Koncentracija odnosa estradiol/progesteron je bila mjerena u skupini žena s FBD (n=50) (studijska skupina) i u kontrolnoj skupini žena bez FBD (n=40) (kontrolna skupina). Sve su žene imale redovite ovulacijske cikluse. Krvni uzorci estradiola (E2), progesterona (P) i prolaktina određivali su se u 8 h ujutro 21. i 24. dana menstruacijskog cikusa. Određivanje značajnosti mastalgije i mastodinije bila je ispitana upitnikom da/ne. Dijagnoza FBD je bila potvrđena ultrazvukom dojke (veličina i broj jednostavnih cista). U kontrolnoj skupini smanjen odnos E2/P zabilježen je od 21. do 24. dana ciklusa (od 14,8±11,5 pg/mL do 9,1±6,1 pg/mL; p<0,05), za razliku od žena studijske skupine gdje ta promjena nije bila zapažena. Čak i mala promjena odnosa E2/P može doprinijeti nastanku FBD s kliničkim manifestacijama mastalgije i mastodinije

Individualizacija magistralnog hormonskog liječenja kod bolesnice s kemoterapijom induciranom prijevremenom insuficijencijom jajnika i smanjenom jetrenom funkcijom: prikaz slučaja

Although the use of commercially manufactured hormone therapy (HT) to treat menopausal symptoms has declined during the past 12 years, the use of custom compounded HT seems to have increased. A 39-year-old woman with refractory anemia sustained premature ovarian insufficiency following allogeneic stem cell transplantation. After systemic biologic treatment (azacitidine) and corticosteroid therapy, besides extreme climacteric symptoms (Green Climacteric Scale, 59) and impaired quality of life, she also had elevated liver enzymes. Therefore, she was not a candidate for oral HT. Treatment was started with 17-beta estradiol patch 0.5 mg (Climara) together with micronized progesterone intravaginally, 2x100 mg (Utrogestan) for 3 months. She was not satisfied, so the custom compound HT started with 17-beta estradiol 0.5 mg gel 2x/day and micronized progesterone in liposomal gel 100 mg/daily. She was much better but she complained of low libido, decreased sex drive and emotional instability, so 1% testosterone gel was added. Now she was completely satisfied, Green Climacteric Scale was 8 and liver enzymes were normal. In conclusion, custom compound HT has the possibility of tailoring and adjusting therapy to the individual need, which has been the everlasting goal in menopause medicine and should be a good option for special clinical cases.Premda je upotreba komercijalno pripravljene hormonske terapije u liječenju klimakteričnih simptoma u posljednjih 12 godina u padu, čini se da je upotreba magistralnih hormonskih pripravaka u porastu. Žena u dobi od 39 godina s refraktornom anemijom doživjela je prijevremenu insuficijenciju jajnika nakon transplantacije matičnih stanica. Nakon sistemskog biološkog liječenja azacitidinom i kortikosteroidima, uz izrazite klimakterične tegobe (Greenov indeks 59) i smanjenu kvalitetu života imala je povišene jetrene enzime. Zbog toga nije bila kandidat za oralnu hormonsku terapiju. Započeto je liječenje 17-beta estradiolom u obliku naljepka od 0,5 mg (Climara) zajedno s mikroniziranim progesteronom intravaginalno 2x100 mg (Utrogestan) kroz 3 mjeseca. Nije bila zadovoljna terapijom pa su joj propisani magistralno pripravljeni hormoni. Započelo se s primjenom 17-beta estradiola u obliku 0,5 mg gela 2x/dan i mikroniziranog progesterona u liposomalnom gelu 100 mg/dnevno. Bolje se je osjećala, ali još uvijek se žalila na smanjeni libido i emocionalnu nestabilnost pa je dodan 1% testosteron. Sad je bila potpuno zadovoljna terapijom, Greenova klimakterijska ljestvica bila je 8, a jetreni enzimi su se normalizirali. U zaključku, magistralni hormonski pripravci pružaju mogućnost titracije i prilagođavanja terapije individualnim potrebama, što je stalni cilj u menopauzalnoj medicini i mogao bi biti dobra mogućnost za posebne slučajeve

The analysis of polymorphism in the genes for the receptors of sex steroids in women with the premature ovarian failure

Prosečna starost za ulazak u menopauzu u populacijama žena zapadnih zemalja je približno 51 godina. Prevremenu disfunkciju ovarijuma (POI) karakteriše amenoreja, hipoestrogenizam i povišeni gonadotropini kod žena mlađih od 40 godina. Uzroci POI su heterogeni, uključujući aberacije X hromozoma, infekcije, jatrogene uzroke (hirurgija, hemoterapija, zračenje) i autoimmune bolesti. Oko 20-30% žena sa POI ima i porodičnu anamnezu, sa ženskim članovima porodice koji nose istu dijagnozu. Stoga je genetska osnova za poremećaj verovatno uzrok ovog kliničkog stanja. Poznato je da normalni razvoj i funkcija jajnika zahtevaju ekspresiju i pravilnu koordinaciju mnogih gena. Navedeni mehanizmi su većinom nepoznati i uprkos genetskim defektima koji su identifikovani u nekoliko gena kandidata, u velikom broju POI slučajeva nije pronađen nijedan uzrok i zato su klasifikovani kao idiopatski POI. S obzirom da su veličina inicijalne folikularne formacije i brzina folikularnog trošenja povezane sa starošću pri menopauzi i s obzirom na činjenicu da ovi zametci ćelija izražavaju gonado steroidne receptore u različitim fazama razvoja, moguće je da genetičke varijante u genima za receptore polnih steroida, koje su uključene u održavanje funkcije jajnika, mogu uticati na rizik od PPOI. Osnovni modulatori folikulogeneze su estrogenski receptori (ERα i ERβ) koji direktno kroz regulisanje hipofiza-gonadne ose omogućavaju delovanje estrogena. Sekventni polimorfizam ERα gena (ESR1:estrogen receptor 1) je pokazao povezanost sa osteoporozom, neobjašnjivom neplodnošću, nižim odgovorom na stimulaciju jajnika, fibromima u materici i endometriozom. Nedavna istraživanja su pokazala da su mikrosatelitni polimorfizmi gena za ESR1 povezani sa PPOI u korejskoj kohorti. Nedostatak estrogena povezan je sa povećanim poremećajem kostiju, ubrzanim gubitkom kostane mase što dovodi do povećane podložnosti osteoporozi i frakturi kostiju. Nasleđivanje koštane mase je pod poligenskom kontrolom. SOHLH1 i SOHLH2 geni su faktori transkripcije vazni za razvoj PPOI. SOHLH2 gen nalazi se na 13 hromozomu, i jedan je od testis-specifičnih faktora koji su od suštinske važnosti za spermatogenezu, ovogenezu i folikulogenezu. SOHLH 1 i 2 geni su izraženi isključivo u primordijalnim folikulima do primarne folikularne faze i predstavljaju master regulatore gena jajne ćelije odgovorne za rani rast i diferencijaciju folikula...The average age for menopause in Western populations is approximately 51 year. Premature ovarian failure (PPOI) is characterised by amenorrhoea, hypoestrogenism and elevated gonadotropins and affects of women under the age of 40. The causes of PPOI are heterogeneous, including chromosome X defects, infections, iatrogenic (surgery, chemotherapy, radiation), and autoimmune disease. Approximately 20-30% of women with PPOI will have other affected female members, hence a genetic basis for the disorder is a likely cause for this clinical scenario. It is known that normal ovarian development and function require the expression and proper coordination of many genes. The underlying mechanisms are largely unknown and despite the genetic defects identified in several candidate genes, in a large proportion of PPOI cases no cause has been found; and hence they are classified as idiopathic PPOI. Considering that initial follicular pool size and the rate of follicular depletion are associated with the age of menopause and given the fact that these germ cells express gonadal steroid receptors at various stages of development, it is plausible that genetic variants in sex hormone receptor genes involved in maintaining ovarian function could affect the risk of PPOI. Estrogen actions mediated through its cognate receptors (ERα and ERβ) are essential modulators of folliculogenesis, directly throught regulation of the hypophyseal-gonadas axis. Sequence polymorphisms of the ERα gene (ESR1: estrogen receptor 1) have been shown to be associated with osteoporosis, unexplained infertility and lower response to ovarian hyperstimulation, and uterine fibroids and endometriosis. A recent study reports that ESR1 gene polymorphisms are associated with PPOI in Korean cohort. Deficiency of estrogen, a critical reproductive hormone for bone acquisition, is associated with an increased bone turnover and accelerated bone loss, leading to the increased susceptibility to osteoporosis and bone fractures. The inheritance of bone mass is under polygenic control.SOHLH 1 and 2 are transcription factors involved in etiology ofPPOI.SOHLH2 gene is situated on chromosome 13 and is testis-specific factor important for spermatogenesis, oogenesis and folliculogenesis. Both, SOHLH 1 and 2,are expressed exclusively in primordial follicles up until the primary follicle stage, and are master regulators of oocyte-specific genes critical for early follicle growth and differentiation..

Radiofrequency as the New Opportunity in Treating Overactive Bladder and Urge Urinary Incontinence—A Single-Arm Pilot Study

Background and Objectives: Until now, overactive bladder (OAB) with or without urge urinary incontinence (UUI) has been treated mainly in two ways: with behavioral methods and patient education, or using antimuscarinic drugs and/or beta-3 adrenergic receptor agonists. Unfortunately, these drugs may cause side effects in some women or are insufficiently effective, so patients abandon them. Therefore, in this pilot study, radiofrequency was evaluated as a new option in the treatment of OAB and UUI. Materials and Methods: Nineteen patients were enrolled in this pilot study using radiofrequency (RF), where the level of OAB and UUI was assessed using the validated ICIQ-OAB questionnaire. RF was applied four times for 20 min, once a week. Two weeks after treatment, the level of OAB and UUI was reassessed and processed statistically and the treatment effect evaluated. Results: Using the ICIQ-OAB, the severity of OAB and UUI was assessed: 0–3 mild symptoms; 4–7 moderate symptoms; 8–11 severe symptoms; 12–16 very severe symptoms. Before treatment, 10.5% of patients had mild symptoms, 21.1% moderate symptoms, 63.2% severe symptoms and 5.3% very severe symptoms. After treatment, 42.9% had mild symptoms, 50% moderate symptoms and 7% severe OAB and UUI symptoms. All four main symptoms—frequency, nocturia, urgency and incontinence—decreased statistically significantly, with the best results being found in urgency (p = 0.002). Conclusions: Based on this pilot study, RF seems a very promising method in the treatment of OAB and UUI. To extend our initial findings, it is necessary to perform a prospective, randomized and placebo-controlled study in order to obtain reliable results and to determine for how long one set of treatment maintains the results obtained immediately after the end of that treatment. In this way, we may determine how often the treatment needs to be repeated, if necessary, and when

Genetska etiologija prijevremene insuficijencije jajnika

Primary premature ovarian insufficiency (PPOI) is characterized by hypergonadotropic amenorrhea and hypoestrogenism in women under 40 years of age. PPOI incidence is 1:10,000 in women aged 18-25, 1:1000 in women aged 25-30 and 1:100 in women aged 35-40. In 10%-28% of cases, PPOI causes primary and in 4%-18% secondary amenorrhea. The process is a consequence of accelerated oocyte atresia, diminished number of germinated cells, and central nervous system aging. Specific genes are responsible for the control of oocyte number undergoing the ovulation process and the time to cessation of the reproductive function. A positive family history of PPOI is found in 15% of women with PPOI, indicating the existing genetic etiology. Primary POI comprises genetic aberrations linked to chromosome X (monosomy, trisomy, translocation, deletion) or to autosomal chromosome. Secondary POI implies surgical removal of ovaries, chemotherapy and radiotherapy, and infections. Diagnostic criteria include follicle stimulating hormone level >40 IU/L and estradiol level <50 pmol/L.Primarna prijevremena insuficijencija jajnika (PPIJ) je sindrom koji je obilježen hipergonadotropnom amenorejom i hipoestrogenizmom. Incidencija PPIJ je 1:10.000 kod žena starosti 18-25 godina, 1:1000 kod žena starosti 25-30 godina i 1:100 kod žena starosti 35-40 godina. U 10%-28% slučajeva PPIJ je uzrok primarnih, a u 4%-18% sekundarnih amenoreja. Bolest nastaje kao posljedica ubrzanog procesa atrezije oocita, smanjenja broja germinativnih stanica i starenja središnjeg živčanog sustava. Specifični geni su odgovorni za kontrolu broja oocita koji prolaze proces ovulacije i vrijeme prekida reproduktivne funkcije. Pozitivna obiteljska anamneza PPIJ nađena je u oko 15% žena s PPIJ, što ukazuje na postojanje određene genetske etiologije. Primarna insufi cijencija jajnika (PIJ) dijeli se na primarnu i sekundarnu. U primarnu PIJ spadaju genetske aberacije vezane za kromosom X (monosomije, trisomije, translokacije, delecije) ili one vezane za autosomne kromosome. U sekundarnu PIJ spadaju kirurško odstranjenje jajnika, liječenje kemoterapijom i radioterapijom te infekcije. Simptomi su razdražljivost, nemir, gubitak libida, depresija, nesanica, dekoncentracija, napadaji vrućine, povišenje tjelesne težine, suhoća vagine i drugih sluznica. Kriteriji za dijagnozu su folikulostimulirajući hormon viši od 40 IJ/L i estradiol (E2) niži od 50 pmol/L kod žena mlađih od 40 godina

Platelet-rich plasma (PRP) for the treatment of vulvar lichen sclerosus in a premenopausal woman: A case report

The use of platelet-rich plasma (PRP) for the treatment of lichen sclerosus (LS) in a 38-year-old premenopausal woman is reported. The diagnosis was confirmed histologically and the symptoms documented using the ICIQ Vaginal Symptoms Questionnaire (ICIQ-VS) and the Female Sexual Function Index (FSFI) questionnaire. PRP was prepared from autologous blood using the Regen Cellular Matrix Kit. PRP was administered twice over two months. Histology at follow-up one month after the second administration showed the epidermis was nearly normal and upper dermal cellularity had been restored. The patient was symptom-free and both her ICIQ-VS and her FSFI scores had improved significantly. PRP is a potential new treatment option for LS which needs further assessment in randomized controlled trials. Keywords: Platelet-rich plasma, Vulvar lichen sclerosus, Premenopause, Treatmen

The Role of E2/P Ratio in the Etiology of Fibrocystic Breast Disease, Mastalgia and Mastodynia

The aim of the study was to assess the role of the estradiol and progesterone relationship during the late luteal phase and the occurrence of fibrocystic breast disease (FBD). The concentration of estradiol/progesterone was measured in the group of women with FBD as study group (n=50) and control group of women without FBD (n=40). All women had regular ovulation cycles. Blood samples for estradiol (E2), progesterone (P) and prolactin determination were obtained in the morning at 8 am on days 21 and 24 of menstrual cycle. Significant mastalgia and mastodynia history in women with FBD was obtained with yes or no questionnaire. FBD diagnosis was confirmed with ultrasound (size and number of simple cysts). In the control group, a reduced E2/P ratio was noticed from day 21 to day 24 of the cycle (from 14.8±11.5 pg/mL to 9.1±6.1 pg/mL; p<0.05), which was not recorded in the group of women with FBD (study group). Even the slightest disturbance of the E2/P ratio may contribute to the occurrence of FBD with clinical manifestations of mastalgia and mastodynia

Genetic etiology of primary premature ovarian insufficiency

Primary premature ovarian insufficiency (PPOI) is characterized by hypergonadotropic amenorrhea and hypoestrogenism in women under 40 years of age. PPOI incidence is 1:10,000 in women aged 18-25, 1:1000 in women aged 25-30 and 1:100 in women aged 35-40. In 10%-28% of cases, PPOI causes primary and in 4%-18% secondary amenorrhea. The process is a consequence of accelerated oocyte atresia, diminished number of germinated cells, and central nervous system aging. Specific genes are responsible for the control of oocyte number undergoing the ovulation process and the time to cessation of the reproductive function. A positive family history of PPOI is found in 15% of women with PPOI, indicating the existing genetic etiology. Primary POI comprises genetic aberrations linked to chromosome X (monosomy, trisomy, translocation, deletion) or to autosomal chromosome. Secondary POI implies surgical removal of ovaries, chemotherapy and radiotherapy, and infections. Diagnostic criteria include follicle stimulating hormone level >40 IU/L and estradiol level <50 pmol/L