Ebook Frontiers in gynecological endocrinology (Volume 3: Ovarian function and reproduction - From needs to possibilities): Part 2

Continued part 1, part 2 of ebook Frontiers in gynecological endocrinology (Volume 3: Ovarian function and reproduction - From needs to possibilities) provide readers with content about: PCO, metabolism, vitamin D, myoma and endometriosis; menopause and ageing; hormone therapies; gender-specific hypertension;... Please refer to the part 2 of ebook for details!

PCO, Metabolism, Vitamin D, Myoma

and Endometriosis

© International Society of Gynecological Endocrinology 2016

A.R Genazzani, B.C Tarlatzis (eds.), Frontiers in Gynecological Endocrinology:

Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities,

ISGE Series, DOI 10.1007/978-3-319-23865-4_13

F Facchinetti (*) • G Dante • I Neri

Mother-Infant Department , University of Modena and Reggio Emilia , Modena , MO , Italy

e-mail: fabio.facchinetti@unimore.it

13

The Ratio of MI to DCI and Its Impact

in the Treatment of Polycystic Ovary

Syndrome: Experimental and Literature

of infertility, affecting approximately up to 10 % of women in reproductive age Although MI and DCI exert different physiological functions, their respective roles

in the etiology and treatment of PCOS are still debated

endoge-(DCI), another biologically relevant stereoisomer, is enzymatically converted from

MI through an insulin-dependent epimerase Despite their similarities, MI and DCI display different biological function Considering that glucose metabolism is regu-lated by insulin whereas the activation of glucose transporters and glucose utiliza-tion are due to MI, the glycogen synthesis is controlled through DCI [ 4 6 ] On the other hand, MI in the ovary is devoted to glucose uptake and FSH signaling, while DCI mediates insulin-induced testosterone synthesis MI constitutes almost all (>99 %) INS in the intracellular pool of most tissues, whereas the remainder is DCI Noteworthy, every tissue has its own specifi c MI:DCI ratio, which translates into the different tissue function [ 7 ] Accordingly, in order to set a proper treatment for PCOS, it is necessary to restore and maintain the appropriate MI:DCI ratio In this chapter, we will report, for the fi rst time, MI and DCI plasma ratio in healthy subjects, discussing the trials that have investigated a therapeutic option based on this ratio and some results of the international consensus conference held on myo- inositol and d -chiro-inositol in obstetrics and gynecology

13.3 MI:DCI Physiological Plasma Ratio

We identifi ed two studies [ 8 , 9 ], both from the same group, reporting the kinetic (PK) profi le of a pharmaceutical preparation of MI In these studies were measured MI plasma levels, but also DCI levels were recorded We had permission from the authors to access their data to calculate the physiological plasma ratio from each study Study 1 was performed in 20 volunteers (eight males, 12 females), aged between 18 and 35 years, with a body mass index (BMI) ranging between 21 and

pharmaco-25 kg/m 2 Study 2 was performed in 12 volunteers (all women) aged between 20 and

40 years with a BMI between 18 and 24 By pooling data from the two studies, we have found a MI:DCI ratio of 40:1 (Fig 13.1 )

Study 1 Study 2

Study 1+2

0 10 20 30 40 50

Fig 13.1 Plasma ratio

(40:1) and

pharmacokinetics of MI

and DCI Data of two

different studies in human

volunteers

nurtur-turn could impair hormone signaling, namely, of both insulin and FSH

Various evidences supported a defi ciency concerning the availability and/or utilization of MI and/or DCI in tissues of PCOS women, and this impairment likely contributes to the insulin resistance typical of that syndrome [ 6 , 10 ] Unlike other tissues, such as muscles and liver, the ovaries are not insulin resistant Because the epimerase activity, regulating the MI:DCI ratio, is insulin dependent, PCOS patients are affected by a boosted MI to DCI epimerization into the ovary, leading to overproduction of DCI and MI defi ciency [ 11 ], as shown by two inde-pendent laboratories [ 6 , 10 ] Thus, a specifi c MI depletion and a DCI overload characterize the ovary of PCOS women The poor oocyte quality observed in PCOS patients can be explained by this imbalance, responsible also for the impaired FSH signaling [ 12 , 13 ]

Literature evidences have already shown that MI supplementation is able to rect PCOS metabolic aspects Two trials demonstrated that the same effect was

cor-obtained even in a more effective way by administering MI and DCI in a cal ratio (40:1) Indeed, the improved parameters were diastolic blood pressure, fasting glucose, fasting insulin, and both insulin and glucose AUCs [ 14 , 15 ] Additional improved parameters were those linked to the CVD, namely, HOMA index, triglycerides, and both HDL and LDL cholesterol Noteworthy, ovulation was restored in the majority of the women

Furthermore, by moving from the metabolic aspects of the syndrome to the reproductive ones, a trial has shown that the treatment of PCOS women undergoing ICSI, with a MI:DCI 40:1 based therapy, retains the benefi cial effects of MI treat-ment alone, outperforming the DCI treatment [ 12 ]

In particular, the treatment is able to improve ovarian response and oocyte and embryo quality Recently, the interest of the scientifi c world on MI and DCI has pushed the PRESIS to organize an international consensus conference in order to clarify this issue and lay the foundations of future researches

13.4 Conference Aim and Methods

Since the knowledge of the differences between MI and DCI is not well lished among researchers, as it is proven by a systematic and a Cochrane review mixing trials performed using MI or DCI, the PREIS School (Permanent International and European School in Perinatal Neonatal and Reproductive Medicine) has organized the “2013 Florence International Consensus Conference

estab-on Myo and d -chiro- inositol in Obstetrics and Gynecology and Assisted Reproduction Technology (ART)” aimed at elucidating some controversial points with the contribution of opinion leaders in the fi elds of cell biology, mammalian embryology, human endocrinology, metabolism, obstetrics, and

13 The Ratio of MI to DCI and Its Impact in the Treatment of Polycystic Ovary

gynecology Two separate panels of this Committee worked on the roles of MI:DCI in metabolic syndrome (mainly PCOS) therapy and of MI in ART and drew up two lists of hot topics Our review reports only the published results in the paper on myo-inositol and ART [ 16 ]

The following is a set of research questions concerning ART:

1 Physiological involvement of INS in oocyte maturation

2 INS involvement in the physiology of spermatozoa function

3 Usefulness of the treatment with INS during ART cycles

4 Comparison of the clinical efficacy between supplementation with MI and/

or DCI

13.5 MI and ART

13.5.1 Physiological Involvement of INS in Oocyte Maturation 13.5.1.1 Role of MI in Oogenesis and Early Embryogenesis

In mammalian females including humans, an elevated MI content in the follicular

fl uid fosters oocyte quality and pregnancy outcome [ 17 , 18 ] MI activity is in nection with the InsP3 function on the modulation of intracellular calcium ion concentration, infl uenced by LH and FSH hormones [ 16 ] In oocytes, MI, among different functions at the ovarian level, positively affects the maturation process [ 16 ] The decrease of intracellular MI stores impairs oocyte maturation, and MI supplementation in culture medium has been shown to increase the development of fertile eggs [ 16 ] The implantation rate and post-implantation viability of embryos rise if the oocytes are cultured in a medium containing MI and then fertilized

con-in vitro and transferred for promotcon-ing pregnancy [ 16 – 19 ] During in vitro tion (IVF) cycles, the treatment of women with MI before the hormonal stimula-tion has reduced the FSH quantity to be administered and the number of days required for the appropriate stimulation All these parameters are positively related

fertiliza-to the possibility of pregnancy and improved quality of oocytes and embryos and, probably, the implantation rate [ 12 , 16 ] Thus, MI administered 3 months before ovulation induction can produce a rise in the number of high-quality embryos obtained in IVF cycles

13.5.1.2 MI and Oogenesis: A Lesson from Polycystic

Ovary Syndrome

Further proofs confi rming the essential role of MI in follicular fl uid for safeguarding egg quality derived from the PCOS studies were previously examined It is therefore clear that MI depletion in a PCOS ovary impairs dominant follicle recruitment and appropriate oocyte growth/maturation These data support the fundamental obser-vations by Chiu et al [ 18 ] showing that proper content of MI in follicular fl uid indicates a required condition to ensure egg quality

condi-MI, which is implicated in processes such as the regulation of spermatozoa motility, capacitation, and acrosome reaction MI increases sperm cell parameters in male patients suffering from oligoasthenoteratozoospermia (OAT), a severe pathology impairing sperm cell number, morphology, and function [ 16 ] This evidence sug-gests that MI use in the treatment of semen samples during IVF cycles can raise fertilization rate and embryo quality, in this way, giving higher chances of preg-nancy Treating OAT patients’ sperm cells with MI gives the following changes: the presence of amorphous material and semen viscosity decreases, midpiece volume improves, and mitochondrial cristae morphology is restored, regularizing the mito-chondria structures [ 16 ] At the functional level, a key step is the direct MI action on mitochondria, raising the membrane potential [ 16 ] High values of mitochondrial membrane potential attest to the integrity of this structure, meaning, optimal levels

of activity and proper cell viability Therefore, MI treatment of sperm cells from both OAT patients and normal subjects enhances the recovery of cells usable in IVF cycles after swim-up [ 16 ], supporting its use as supplement in sperm cells manipu-lation in the procedures of medical-assisted reproduction

13.5.3 Usefulness of INS Treatment During ART Cycles

As shown before, the pre-treatment of the PCOS patients with MI looks really very encouraging The MI effect has been verifi ed also in non-PCOS women needing fertility treatment owing to male or tubal anomalies [ 16 ] All these data are in keep-ing with the evidence by Chiu et al [ 18 ] that the gonadotropin quantity necessary for ovarian stimulation is lower in patients with follicular fl uid characterized by higher MI levels

13.5.4 Comparison of the Clinical Efficacy Between

Supplementation with MI and/or DCI

As highlighted previously, for exerting its physiological function, the ovary would not need high doses of DCI Moreover, the poor oocyte quality in PCOS ovary could

be caused by decreased energy metabolism, and in turn, it is an effect of the down- regulation of the genes controlling glucose uptake [ 13 , 20 ] These fi ndings agree with those obtained by Unfer et al [ 12 ], showing that MI but not DCI exerts an action at the ovarian level and leading to the previously quoted DCI paradox Therefore, the positive MI activity on oocyte quality could be related with its

13 The Ratio of MI to DCI and Its Impact in the Treatment of Polycystic Ovary

function in glucose cell uptake, which ameliorates the energy status of the ovary, and in FSH signaling and induction of calcium release, which allows proper germ cell maturation

Conclusions

Experimental data demonstrated that in the baseline condition, the MI:DCI ratio

in healthy volunteers is set at 40:1 According to the International Consensus Conference, it is now clear that both MI and DCI are involved in various physi-ological and pathological functions (mainly the transduction of insulin and FSH signal), although with differentiated roles INS supplementation could exert a positive action in different pathophysiological features in obstetrics and gynecology The MI supplementation is very promising, with clear benefi ts, in the treatment of PCOS women and also in the prevention of gestational diabetes mellitus A much larger amount of clinical data are available for MI in comparison with DCI, but the existence of tissue-specifi c ratios also in the ovary has sug-gested to develop a treatment based on both MI:DCI combination (ratio 40:1), in agreement with the “DCI paradox” [ 11 ]

On the other hand, INS by itself or through its derivatives exerts a pivotal role

in reproduction, namely, in oocyte and spermatozoa development MI depletion induces a defect in glucose uptake, reducing glucose availability in the ovary for both oocytes and follicular cells The impairment of sugar availability in oocytes compromises their quality [ 21] MI treatment in ART has demonstrated undeniable positive effects, and the use of MI, alone or in combination with DCI,

at the 40:1 ratio, should be defi nitely considered a predictive factor for the improvement of ART outcome

3 Clements RS Jr, Darnell B (1980) Myo-inositol content of common foods: development of a high-myo-inositol diet Am J Clin Nutr 33(9):1954–1967

4 Larner J, Huang LC, Tang G, Suzuki S, Schwartz CFW, Romero G, Roulidis Z, Zeller K, Shen

TY, Oswald AS, Luttrell L (1988) Insulin mediators: structure and formation Cold Spring Harb Symp Quant Biol 53(Pt 2):965–971

5 Sun TH, Heimark DB, Nguygen T, Nadler JL, Larner J (2002) Both myoinositol to chiro- inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues

of GK type 2 diabetic rats compared to Wistar controls Biochem Biophys Res Commun 293:1092–1098

6 Heimark D, McAllister J, Larner J (2014) Decreased myo-inositol to chiro-inositol (m/c) ratios and increased m/c epimerase activity in pcos theca cells demonstrate increased insulin sensi- tivity compared to controls Endocr J 61:111–117

7 Pak Y, Huang LC, Lilley KJ, Larner J (1992) In vivo conversion of [3H] myoinositol to [3H] chiroinositol in rat tissues J Biol Chem 267:16904–16910

8 Carlomagno G, De Grazia S, Unfer V, Manna F (2012) Myo-inositol in a new pharmaceutical form: a step forward to a broader clinical use Expert Opin Drug Deliv 9(3):267–271 doi: 10.1 517/17425247.2012.662953

9 De Grazia S, Carlomagno G, Unfer V, Cavalli P (2012) Myo-inositol soft gel capsules may prevent the risk of coffee-induced neural tube defects Expert Opin Drug Deliv 9(9):1033–

1039 doi: 10.1517/17425247.2012.701616 , Epub 2012 Jul 5

10 Unfer V, Carlomagno G, Papaleo E, Vailati S, Candiani M, Baillargeon JP (2014) Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fl uid of patients with PCOS Reprod Sci 21:854–858

11 Carlomagno G, Unfer V, Roseff S (2011) The D-chiro-inositol paradox in the ovary Fertil Steril 95:2515–2516

12 Unfer V, Carlomagno G, Rizzo P, Raffone E, Roseff S (2011) Myo-inositol rather than D-chiro- inositol is able to improve oocyte quality in intracytoplasmic sperm injection cycles A pro- spective, controlled, randomized trial Eur Rev Med Pharmacol Sci 15:452–457

13 Arya BK, Haq AU, Chaudhury K (2012) Oocyte quality refl ected by follicular fl uid analysis in polycystic ovary syndrome (PCOS): a hypothesis based on intermediates of energy metabo- lism Med Hypotheses 78:475–478

14 Nordio M, Proietti E (2012) The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone Eur Rev Med Pharmacol Sci 16:575–581

15 Minozzi M, Nordio M, Pajalich R (2013) The combined therapy myo-inositol plus D-chiro- inositol, in a physiological ratio, reduces the cardiovascular risk by improving the lipid profi le

in PCOS patients Eur Rev Med Pharmacol Sci 17:537–540

16 Bevilacqua A, Carlomagno G, Gerli S, Montanino Oliva M, Devroey P, Lanzone A, Soulange

C, Facchinetti F, Di Renzo GC, Bizzarri M, Hod M, Cavalli P, D’Anna R, Benvenga S, Chiu

TT, Kamenov ZA (2015) Results from the International Consensus Conference on myo- inositol and D-chiro-inositol in Obstetrics and Gynecology – assisted reproduction technology Gynecol Endocrinol doi: 10.3109/09513590.2015.1006616

17 Chiu TT, Tam PP (1992) A correlation of the outcome of clinical in vitro fertilization with the inositol content and embryotrophic properties of human serum J Assist Reprod Genet 9:524–530

18 Chiu TT, Rogers MS, Law EL, Briton-Jones CM, Cheung LP, Haines CJ (2002) Follicular

fl uid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality Hum Reprod 17:1591–1596

19 Colazingari S, Fiorenza MT, Carlomagno G, Najjar R, Bevilacqua A (2014) Improvement of mouse embryo quality by myo-inositol supplementation of IVF media J Assist Reprod Genet 31:463–469

20 Ma X, Fan L, Meng Y, Hou Z, Mao YD, Wang W, Ding W, Liu JY (2007) Proteomic analysis

of human ovaries from normal and polycystic ovarian syndrome Mol Hum Reprod 13:527–535

21 Chaudhary K, Babu KN, Joshi VN, Srivastava S, Chakravarty BN (2011) NMR-based lomics reveals differently expressed metabolites in follicular fl uid of PCOS women: potential biomarkers for good quality oocyte? Hum Reprod 26:i226–i246

metabo-13 The Ratio of MI to DCI and Its Impact in the Treatment of Polycystic Ovary

© International Society of Gynecological Endocrinology 2016

A.R Genazzani, B.C Tarlatzis (eds.), Frontiers in Gynecological Endocrinology:

Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities,

ISGE Series, DOI 10.1007/978-3-319-23865-4_14

Metabolic Healthy Obesity

and Metabolic Obesity with Normal

Weight and CVD Risk in Women

Andrzej Milewicz and Eliza Kubicka

Obesity is defi ned as the excess of body fat and results from interactions between genes and the environment The factors contributing to obesity are unsuitable nutri-tion and food overproduction, poor physical activity, mental stress, psychoemo-tional disorders, and metabolic and hormonal disturbances [ 1 ]

Among gene candidates predisposing to obesity mutations and polymorphism of the gene of insulin receptor, polymorphism of the gene of PPARγ receptor, poly-morphism of the gene of glucocorticoid receptor, and polymorphism of the gene of β3-adrenergic receptor are mentioned [ 2 5 ]

To evaluate obesity, body mass index (BMI) is useful (BMI = body weight in kg and high m 2 ratio) Obesity is diagnosed when BMI is above 30 kg/m 2 , whereas overweight is when BMI is above 25 kg/m 2 Also fatty tissue percentage (>25 % of body mass in males and >30 % in females) is useful in obesity evaluation To esti-mate fat distribution, waist-to-hip ratio (WHR, >1.0 in males and >0.8 in females) and waist circumference (>80 cm in females and >94 cm in males) can be used More accurate methods used to evaluate fat mass are dual-energy X-ray absortiom-etry and computed tomography

In order to evaluate abdominal fat, a dual-energy X-ray absorptiometry (DXA) is used where androidal deposit is assessed at L 2 –L 4 level [ 6 ] The “gold standard” to determine the visceral and subcutaneous abdominal fat is through computer tomogra-phy The evaluation is performed at the level of the intervertebral lumbar disc L 4 –L 5 [ ] The adipose tissue is not only a fat storage but also an active endocrine organ which produces and secretes many hormones and protein factors and plays an important role in metabolic homeostasis Adipocytes contain over 20 hormone receptors and products or release numerous protein and non-protein substances

which play a signifi cant role in the immune system (TNFα, Il-6, TGFβ), blood sure (angiotensinogen), blood coagulation (PAI-1), glycemic homeostasis (adipo-nectin, resistin, visfatin, leptin), and angiogenesis (VEGF) [ 8 ]

The visceral adipose tissue (VAT) differs from the subcutaneous fat (SCAT) tomically, hormonally, and metabolically; excessive amount of the former type has been postulated as the key causative factor for metabolic disturbances Visceral fat

ana-is characterized by high density of β-adrenergic, resistin, androgen, and coid receptors, which impair insulin sensitivity Adipocytes in this localization are also resistant to insulin lipogenic effects and more lipolytic Additionally, adipocy-tokines are released directly to the portal venous system and infl uence and affect carbohydrates and lipids metabolism Visceral fat may enhance truncal SCAT lipol-ysis as well Production of infl ammatory markers (IL-6) and prothrombotic factors (PAI-1) is higher in visceral adipose tissue than in subcutaneous adipose tissue Preadipocytes of the subcutaneous adipose tissue have a greater differentiation and may replenish VAT Localized subcutaneous adipocytes secrete relatively more atheroprotective adiponectin and leptin while less resistin compared to that

glucocorti-of visceral adipose tissue cells, which leads to insulin sensitivity improvement is associated with female phenotype characterized by higher subcutaneous fat accumulation

Fat distribution depends on gender, age, and ethnicity For example, Asian and Japanese people have lower deposits of the visceral fat than Caucasians In men, visceral fat deposits reach 20 % of the whole fat pool; in pre-menopausal women, from 5 to 8 %

Depending on the body fat distribution and metabolic disturbances presence, there may be mentioned healthy controls, healthy obesity, obesity with metabolic disorders, and obesity with metabolic disorders and normal weight people

Depending on biological age and gender (20–35 % in women, 29 % in men), more often in women and elderly ones, people with a BMI >30.0 kg/m 2 show the metabolic healthy obesity (MHO) phenotype without insulin resistance, dyslipid-emia, or hypertension MHO people have waist circumference ≤80 cm, adipose tissue mass >35 %, fasting glucose level <100 mg/dl, serum triglycerides level

≤150 mg/dl, HDL cholesterol >50 mg/dl, and blood pressure ≤130/85 mmHg Fat accumulates mainly in the region of the hips, buttocks, and thighs with slim waist This phenotype is characterized by the early development of obesity (before 20 years of age, in 13 % – already in childhood) and increased subcutaneous fat con-tent, excluding the pathological deposition of fat in the liver, muscles, and visceral area Histologically fatty tissue in people with MHO is characterized by decreased size and number of adipocytes A relationship between the onset and duration of obesity and insulin sensitivity of tissues as the adaptation mechanism has been pos-tulated [ 9 ] In individuals with this obesity phenotype, an excess of energy delivered with food is directed to subcutaneous fat deposits and/or burnt in the hepatic mito-chondria or the muscles Therefore, the positive energy balance does not increase risk of metabolic disorders The signifi cantly elevated subcutaneous fat deposit and its ratio to visceral fat deposit reveals protective effect against atherosclerosis and metabolic syndrome [ 10 , 11 ] The candidate genes postulated to these modifi ca-tions are endocanabinoid receptor gene (CNR1), 1 adiponectin receptor gene

A Milewicz and E Kubicka

(ADIPOR1), and hepatic lipase factor 1 (LIPC-OMIM 15167) [ 12 ] Individuals with this phenotype reveal increased physical activity compared with those with obesity with metabolic disorders and more advantageous effect on waist circumfer-ence Differences in the diet of individuals with this obesity phenotype have not been evaluated [ 13 , 14 ] The epidemiological study with 5440 participants in the National Health and Nutrition Examination Surveys 1999–2004 did not reveal an increase in the number of stroke episodes or cardiovascular diseases in individuals with MHO in relation to people with normal BMI on follow-up [ 15 ] Observation is recommended because people with MHO who change their physical activity and dietary habits may lead to metabolic syndrome In therapy, only increase of physical activity is recommended [ 16 ]

Metabolic obesity with normal weight (MONW) affects 13–18 % of women aged 20–60 Due to the lack of visible abnormalities, this is diffi cult to identify Very often, it is diagnosed in women with polycystic ovary syndrome In the patho-genesis of these disturbances, increased expression of 11β-hydroxysteroid dehydro-genase type 1 can be suggested [ 17 ] From other abnormalities, in people with MONW, decreased energy use after effort was observed, as well as pathological storage of fat in muscles and liver with decreased storage of fat in subcutaneous adipose tissue The increased hepatic lipase expression is also postulated [ 18 ] People with MONW have some metabolic disturbances like fasting glucose level

≥100 mg/dl, serum triglycerides level ≥150 mg/dl, HDL cholesterol ≤50 mg/dl, and hypertension ≤130/85 mmHg despite normal anthropometric parameters: waist circumference ≤80 cm, BMI ≤25 kg/m 2 , adipose tissue mass ≤35 % [ 19 , 20 ] In the DXA, abdominal fat deposit increased in these subjects in relation to the control group of healthy individuals (Fig 14.1 ) [ 21 ]

Fig 14.1 Abdominal to gynoid deposit ratio (A/G ratio) in different obesity phenotypes of

post-menopausal women Abbreviations: MONW, metabolic obesity with normal weight; MHO, bolic healthy obesity; OWMD, obesity with metabolic disorders

Serum level of atheroprotective adiponectin in subjects with metabolic healthy obesity is signifi cantly higher in comparision with those with obesity with meta-bolic disorders; likewise, serum level of adiponectin in control subjects with nor-mal weight without metabolic disturbances is higher in comparison with those with metabolic obesity with normal weight (Fig 14.2 )

The adipose tissue distribution is connected with three main obesity phenotypes:

“healthy” obesity, obesity with metabolic disorders, and metabolic obesity with mal weight The excessive visceral fat deposit and the pathological storage of fat in muscles and liver play a key role in metabolic disorders

The occurrence of metabolic disorders and higher visceral fat deposit in these patients qualifi es for lifestyle modifi cation and pharmacotherapy Who should be treated then? These should be patients with diagnosed obesity with metabolic disor-ders and metabolic obesity with normal weight Clinical indictaions fot treatment are waist circumference >80 cm in females and >94 cm in males, BMI >30.0 kg/m 2 , adipose tissue mass >35 %, fasting glucose level ≥100 mg/dl, serum triglycerides level >150 mg/dl, HDL cholesterol in females <50 mg/dl and in males <40 mg/dl, and hypertension >130/85 mmHg Metformin is recomended in pharmacological theraphy There are data that metformin induces alterations in the body composi-tion: reduces total fat tissue mass by 7 % and visceral fat mass by 15 %

3 Hara M, Alcoser SY, Qaadir A, Beiswenger KK, Cox NJ, Ehrmann DA (2002) Insulin tance is attenuated in women with polycystic ovary syndrome with the Pro(12)Ala polymor- phism in the PPARgamma gene J Clin Endocrinol Metab 87(2):772–775

Fig 14.2 Serum level of adiponectin (μg/ml) * p < 0.001

A Milewicz and E Kubicka

4 Buemann B, Vohl MC, Chagnon M, Chagnon YC, Gagnon J, Pérusse L, Dionne F, Després JP, Tremblay A, Nadeau A, Bouchard C (1997) Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus Obes Res 5(3):186–192

5 Widén E, Lehto M, Kanninen T, Walston J, Shuldiner AR, Groop LC (1995) Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns N Engl J Med 333(6):348–351

6 Snijder MB, Van Dam RM, Visser M, Seidell JC (2006) What aspects of body fat are larly hazardous and how do we measure them? Int J Epidemiol 35(1):83–92

7 Larson DE, Hunter GR, Williams MJ, Kekes-Szabo T, Nyikos I, Goran MI (1996) Dietary fat

in relation to body fat and intraabdominal adipose tissue: a cross-sectional analysis Am J Clin Nutr 64(5):677–684

8 Kershaw EE, Filer JS (2004) Adipose tissue as an endocrine organ J Clin Endocrinol Metabol 89(6):2548–2556

9 Karelis AD, St-Pierre DH, Conus F, Rabasa-Lhoret R, Poehlman ET (2004) Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 89(6):2569–2575

10 Snijder MB, Visser M, Dekker JM, Goodpaster BH, Harris TB, Kritchevsky SB, De Rekeneire

N, Kanaya AM, Newman AB, Tylavsky FA, Seidell JC, Health ABC Study (2005) Low taneous thigh fat is a risk factor for unfavourable glucose and lipid levels, independently of high abdominal fat The Health ABC Study Diabetologia 48(2):301–308, Epub 2005 Jan 20

11 Demerath EW, Reed D, Rogers N, Sun SS, Lee M, Choh AC, Couch W, Czerwinski SA, Chumlea WC, Siervogel RM, Towne B (2008) Visceral adiposity and its anatomical distribu- tion as predictors of the metabolic syndrome and cardiometabolic risk factor levels Am J Clin Nutr 88(5):1263–1271

12 Jourdan T, Djaouti L, Demizieux L, Gresti J, Vergès B, Degrace P (2010) CB1 antagonism exerts specifi c molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice Diabetes 59(4):926–934 doi: 10.2337/db09-1482

13 Milewicz A, Jedrzejuk D, Dunajska K, Lwow F (2010) Waist circumference and serum nectin levels in obese and non-obese postmenopausal women Maturitas 65(3):272–275

14 Wildman RP (2009) Healthy obesity Curr Opin Clin Nutr Metab Care 12(4):438–443

15 Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, Sowers MR (2008) The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the

US population (NHANES 1999–2004) Arch Intern Med 168(15):1617–1624

16 Perseghin G (2008) Is a nutritional therapeutic approach unsuitable for metabolically healthy but obese women? Diabetologia 51(9):1567–1569

17 Paterson JM, Morton NM, Fievet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR, Mullins JJ (2004) Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice Proc Natl Acad Sci U S A 101(18):7088–7093

18 Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S (1998) The metabolically obese, normal- weight individual revisited Diabetes 47(5):699–713

19 Chan JL, Moschos SJ, Bullen J, Heist K, Li X, Kim YB, Kahn BB, Mantzoros CS (2005) Recombinant methionyl human leptin administration activates signal transducer and activator

of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-alpha receptor levels in humans with relative leptin defi ciency J Clin Endocrinol Metab 90(3):1625–1631, Epub 2004 Dec 21

20 De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger Cats V, Orth-Gomér K, Perk J, Pyorälä K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsene T, Wood D, European Association for the Study of Diabetes (EASD), International Diabetes Federation Europe (IDF-Europe), European Atherosclerosis Society (EAS), European Heart Network (EHN), European Society of Cardiology (ESC), European Society of Hypertension (ESH), International Society of Behavioural Medicine (ISBM), European Society of General Practice/Family Medicine (ESGP/FM) (2004) European guidelines on cardiovascular disease prevention in

clinical practice Third Joint Task Force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts) Arch Mal Coeur Vaiss 97(10):1019–1030

21 Lwow F, Dunajska K, Milewicz A, Jedrzejuk D, Kik K, Szmigiero L (2011) Effect of moderate- intensity exercise on oxidative stress indices in metabolically healthy obese and metabolically unhealthy obese phenotypes in postmenopausal women: a pilot study Menopause 18(6): 646–653

A Milewicz and E Kubicka

© International Society of Gynecological Endocrinology 2016

A.R Genazzani, B.C Tarlatzis (eds.), Frontiers in Gynecological Endocrinology:

Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities,

ISGE Series, DOI 10.1007/978-3-319-23865-4_15

We have novel insights into the pathogenesis of endometriosis and are ing the state of the art in clinical markers of endometriosis We know how the adverse health impacts of endometriosis often compromise our patients in diverse ways for years to decades of their lives The cumulative impact of endometriosis on the health of women across the lifespan can be divided into three sets of issues, namely, those of (1) assessment pelvic/intraperitoneal and extraperitoneal compart-ment; (2) treatment by surgical and endocrine modalities, which in spite of ongoing research are the only real tools of treatment we seem to have; and (3) potentially systemic more remote risks, in terms of location (other tissues/organs), malignancy, and disease in the lifespan of a woman

Endometriosis is indeed a disease with a unique pathophysiology We know that

it is a subchronic to chronic predominantly intraperitoneal, but in about 10 % also invasive disease into bowels, urinary tract organs, and distant locations, often pro-gressive and destructive infl ammatory disease that has a massive impact on the health of many postpubertal women Given the known role of chronic infl ammation

as a prominent factor in the occurrence of numerous other diseases, we must

L Mettler (*) • L V Maul

Department of Obstetrics and Gynecology , University of Hospitals Schleswig Holstein ,

Arnold Hellerstr 3/24 , Kiel , Germany

e-mail: profmettler@gmx.de

15

determine the extent to which this process in the intraperitoneal compartment does

or does not continue into systemic infl ammation that creates other health risks Only with a real understanding attitude of this disease we can develop and implement a helping strategy for care of those who suffer from endometriosis as a chronic disease

This article will focus on “endometriomas,” which occur frequently and require surgery or estrogen-suppressive treatment which in spite of our best intentions with surgical or medical/endocrine treatment are frequently unsuccessful and leave morbidity

We, as doctors, may consider endometrioma surgery or an estrogen-suppressive hormonal treatment as easy procedures, but please, let us be aware of how this dis-ease particularly on the ovaries can interfere with life, love, and happiness of our patients

15.2 Material and Methods

At the Department of Obstetrics and Gynecology, University Hospital Kiel in Germany, we analyzed from 1995 to 2004 retrospectively 3057 patient’s medical records and surgical reports In those we histologically verifi ed 550 patients with ovarian endometriotic cysts undergoing either laparoscopic conservative excision or laparotomy Their data regarding general patient characteristics, endometrioma symptoms, and diagnostic and surgical fi ndings were collected from clinical records and reviewed (Fig 15.1 ) Patients characteristics are summarized in Table 15.1 (A and B) In August 2011, these 550 patients with endometriomas were approached via letter and asked to complete and return a questionnaire to the clinic In cases of invalid addresses, the current addresses of the patients were traced by the registra-tion offi ces up to their second change of residence so that a maximum of three attempts were made to contact the patients With a fi nal return rate of 52.5 %, there

Fig 15.1 Transvaginal ultrasonogram of a 6-cm (diameter), left ovarian endometrioma and its

corresponding laparoscopic image

L Mettler and L.V Maul

were 289 patients in the follow-up study In the questionnaire, patients were asked about a postoperative occurrence of another endometriosis cyst, the temporal occur-rence, and dignity Furthermore, possible reoperation rate, operation type, and recurrent pain symptoms (pain lasting >1 week, dysmenorrhea, and dyspareunia) were inquired Patients were questioned about their preoperative and postoperative fertility and whether a planned spontaneous pregnancy with or without complica-tions occurred, and, in cases of infertility and pregnancy, they were asked if artifi cial insemination was successful The recurrence of ovarian endometrioma was defi ned

Table 15.1 Patient characteristics ( n = 550)

(%)

19–24 344 (62.5) 25–30 123 (22.4) >30 40 (7.3)

Previous laparoscopic surgery of ovarian endometrioma 226 (41.1)

Recurrence of fi rst diagnosed ovarian endometrioma b 47 (23.9)

Reoperation rate of fi rst diagnosed ovarian endometrioma b 32 (68.1)

as a positive response to the presence of an endometriosis cyst (as reported by the patient) in the questionnaire In the analysis of recurrence rate, patients with a previ-ous diagnosis of endometriosis were excluded The average follow-up period was 12.9 years with a minimal time of 7.0 years and a maximal time of 16.9 years between operation and follow-up

Data for analysis were recorded using Microsoft (Redmond, Washington) Access software Statistical analysis was performed using Microsoft Excel and SPSS (IBM Corporation, Armonk, New York) programs Patient identifi cation numbers were assigned for granting data protection The percentages are based primarily on the total number; in the absence of information, the corrected proba-

bility is given In the analysis of categorical values, the χ 2 was used The statistical signifi cance level was set at 5 % ( P < 05) The recurrence-free interval probabili-

ties were estimated according Kaplan-Meier method The log-rank test Cox) was used to compare the survival time of two groups with each other In postmenopausal cases, the women were not considered in the postoperative analy-sis of dysmenorrhea [ 1 ]

(Mantel-15.3 Results

At the time of surgery, the mean age of all endometrioma patients was 37.2 (±9.0) years and at follow-up, 50.5 (±9.3) years (Table 15.1 ) Preoperatively younger age, nulliparity, and previous laparoscopic surgery for ovarian endometrioma predicted positively the presence of pain and dysmenorrhea Larger cyst size (>8 cm) was also associated with occurrence of pain, while primary or secondary sterility was associ-ated with a higher rate of dysmenorrhea

Factors associated with recurrence of dysmenorrhea were younger age ( P < 01), nulliparity ( P < 05), and lager cyst size ( P < 05) Previous laparoscopic surgery for ovarian endometrioma ( P < 05) was the only signifi cant risk factor for recurrence of

pain that was found (Table 15.2 )

One hundred ninety-seven patients were initially diagnosed with endometriomas

at the time of surgery, and, of those, 47 patients showed recurrent ovarian trioma (23.9 %) in the follow-up period Of those 47 patients, 68.1 % (32 of 47) underwent a reoperation in the follow-up period (Table 15.1 ) Of those 32 patients,

endome-17 patients (53.1 %) needed 1 reoperation, 9 patients (28.1 %) needed 2 tions, and 6 patients (18.8 %) required ≥3 reoperations due to new endometriosis cysts The probability of a recurrent-free interval was 76.1 % for all primarily diag-nosed endometriomas in our study period

Patients with preoperative pain showed a signifi cantly higher recurrence rate

(log-rank test P = 013) The Kaplan-Meier graph demonstrates that patients without

preoperative pain had a signifi cantly higher recurrence-free interval of 84.7 % when compared with patients with a history of preoperative pain who were recurrence- free only 69.4 % by the end of the follow-up period (Fig 15.2 ) Another statistically signifi cant risk factor for endometrioma recurrence was preoperative dysmenorrhea

(log-rank test P = 013) The Kaplan-Meier curve (Fig 15.3 ) illustrates that women without preoperative dysmenorrhea have a recurrence-free interval of 81.4 %

L Mettler and L.V Maul

compared with a recurrence-free interval of only 66.2 % in women with tive dysmenorrhea.

Other risk factors that were not signifi cant but showed an association with higher recurrence were larger cyst size (>8 cm; rate of recurrence was 33.3 % [5 of 15] vs 16.3 % [15 of 92] in cyst size 5–8 cm and 16.8 % [24 of 143] in cyst size <5 cm), younger age at surgery (<25 years: 6.4 % [3 of 47] in the recurrence cohort vs 2.8 % [8 of 289] in the follow-up cohort), and preoperative cyst rupture (rate of recurrence was 28.6 % [2 of 7] in laparoscopic surgery vs 20.5 % in laparotomy

Table 15.2 Analysis of factors related to the occurrence and recurrence of pain and dysmenorrhea

Factors

Preoperative Postoperative Preoperative Postoperative

P- value ( n = 550)

P- value ( n = 289)

P- value ( n = 550)

P- value ( n = 267)

Younger age (years) <0.01 NS <0.01 <0.01

By courtesy of Maul et al [ 1 ]

NS not signifi cant

Fig 15.2 Probability of recurrence-free interval within the follow-up period in patients with and

without preoperative pain (By courtesy of Maul et al [ 1 ])

In the follow-up period postoperative medical treatment [26 of 101] in the operative cyst rupture group and 15.4 % [18 of 99] in the no-cyst rupture group showed no statistical signifi cant differences

Analyzing the effectiveness of endometrioma surgery, laparoscopy showed the best results in terms of being symptom-free postoperatively After laparoscopic surgery, 49.0 % of the patients were symptom-free, while after laparotomy, only 33.3 % were

By transition from laparoscopy to laparotomy, only 43.7 % were asymptomatic Postoperative medical treatment was given in 56.1 % of the cases (162 of 289) Additional postoperative hormone therapy (gonadotropin-releasing hormone ago-nist, oral contraceptive, medroxyprogesterone acetate, or danazol) led to a higher recurrence of endometrioma, with a recurrence-free interval rate of only 70.5 % versus 82.6 % in those patients who did not receive hormonal therapy (log-rank test

P = 050) (Fig 15.4 ) The recurrence rates in both groups increased constantly with time from diagnostic surgery Comparing combined surgical and hormonal treat-ment with exclusive surgical therapy, the following differences were shown: postop-erative pain in 36.4 % versus 29.1 %, dysmenorrhea in 37.8 % versus 26.0 %, and dyspareunia in 19.1 % versus 18.1 %

The wish for postoperative pregnancy was found by 111 of 289 patients (38.4 %) Combined surgical and hormonal treatment was given to 61 of 111 patients (55.0 %), whereas surgery alone was performed in 50 of 111 patients (45.0 %) Among these patients, the postoperative spontaneous pregnancy rate was 54.1 % (60 of 111) Of these 60 patients, 46 of 111 (41.4 %) had surgical treatment combined with medical treatment and 14 of 111 (12.6 %) had surgery alone A statistically signifi cant dif-

ference ( P < 001) between combined surgical and hormonal therapy and exclusive

surgery was observed

Fig 15.3 Probability of recurrence-free interval within the follow-up period in patients with and

without preoperative dysmenorrhea (By courtesy of Maul et al [ 1 ])

L Mettler and L.V Maul

15.4 Discussion

Risk factors, the effectiveness of endometrioma surgery comparing laparoscopy versus laparotomy, and the effect of additional medical treatment on recurrence and pregnancy rates were analyzed in our retrospective cohort study

The preoperative risk factors observed as having signifi cant predictive value for presence of pain and dysmenorrhea were younger age, previous laparoscopic sur-gery of ovarian endometrioma, and nulliparity Occurrence of pain seemed to be signifi cantly associated with larger cyst size (>8 cm), while primary or secondary sterility was associated with a higher rate of dysmenorrhea Concerning the recur-rent symptoms, younger age, nulliparity, and larger cyst diameter signifi cantly infl u-enced the recurrence of dysmenorrhea, while only previous laparoscopic surgery of ovarian endometrioma was determined as signifi cant risk factor for recurrence of pain [ 1 ] This was also reported by Bussacca et al [ 4 ] and Porpora et al [ 2 ] In agreement with Vercellini et al [ 8 ] a lower incidence of dysmenorrhea in older age

is justifi able due to the postmenopausal changes The medical condition of a patient can be adversely affected by a previous operation, such as laparoscopy or a longer- existing disease with possible adhesion formation as a natural consequence of the surgical trauma [ 2 4 ] Other studies also suggest that adhesions are important for the cause of endometriosis-associated pain, whereas the cyst diameter in contradic-tion to our study has no signifi cant correlation between cyst size and pain symptoms [ 9 , 10 ]

In line with earlier studies that indicate pregnancy as a protective factor for endometriosis- associated pain [ 2 5 ], nulliparity is attributed a predictive value for

Fig 15.4 Probability of recurrence-free interval within the follow-up period in patients with and

without postoperative hormonal treatment (By courtesy of Maul et al [ 1 ])

laparo-≥2 years of observation [ 5 , 8 ] The results of Busacca et al [ 11 ] showed a recurrence

of ovarian endometriomas in 24.6 % at 4 years after surgery These results strongly resemble ours, which showed a recurrence rate of 23.9 % The discrepancy of num-bers in the literature could be due to different observation periods and criteria for the defi nition of recurrence As recurrent endometriosis is among the signifi cant chal-lenges in this disease, reoperation is currently often regarded as the best treatment option, though the extent and duration of the effect of second-line operation remains unclear [ 12 ] In the present follow-up, a reoperation rate of 68.1 % was observed in

32 of 47 patients with recurrent endometrioma who had ovarian endometriomas tially diagnosed at surgery These observations agree with those of Cheong et al [ 13 ] but not with the lower requirement of reoperation in other observations [ 12 , 14 ]

A history of preoperative pain or preoperative dysmenorrhea was shown to be a signifi cant factor associated with higher recurrence rates, which agrees with a study

by Renner et al [ 15 ] In our study, we observed signifi cantly lower recurrence-free intervals for such preoperative complaints In the present study, larger cyst size, as also reported by Kikuchi et al [ 6 ] and Koga et al [ 5 ], younger age at surgery, and preoperative cyst rupture seemed to increase the risk of ovarian endometrioma recurrence An attempt to explain our results regarding preoperative cyst rupture can be derived from the assumptions of Kikuchi et al [ 6 ] that recurrent cysts occur

in the lesions, in which a cystectomy was performed, whereby endometrial cells contacted the peritoneal surface

Regarding the effectiveness of endometrioma surgery, laparoscopy showed the best results in terms of a symptom-free postoperative course and pain reduction Although other investigators mentioned equivalent therapeutic success under lapa-roscopy and laparotomy, the laparoscopic approach is preferred [ 16 ] This could be because of its good tolerance, low morbidity, and low total cost of treatment [ 2 ] or because laparoscopy with sampling for histological investigation is the gold stan-dard for diagnosis of endometriosis in the evaluation of persistent complaints and therefore often used [ 17 ]

The impact of postoperative hormone therapy on ovarian endometriosis remains currently unclear To determine the effect of additional postoperative medical treat-ment, in the present follow-up, patients with hormone therapy (56.1 %) were com-pared with those without (43.9 %) Our study was in line with previous observations [ 2 12 , 18 – 20 ] that patients do not signifi cantly benefi t from additional postopera-tive hormone therapy (gonadotropin-releasing hormone agonist, oral contraceptive, medroxyprogesterone acetate, or danazol) in terms of reducing the risk of disease and pain recurrence We observed even lower probabilities for a recurrence-free interval referring to an average of 12.9 years of follow-up in patients receiving hor-mone therapy versus patients with exclusive surgical therapy A retrospective study [ 5 ] indicated previous medical treatment of endometriosis as a signifi cant risk factor

( P = 009) for higher recurrence Yap et al [ 21 ] indicated that there was a signifi cant

L Mettler and L.V Maul

improvement in the recurrence rate after postoperative hormone intake, but pared with exclusive surgery, there were no benefi cial effects on pain and pregnancy rate recorded

Among the 111 patients with a desire to become pregnant, the postoperative spontaneous pregnancy rate was 54.1 %, correlating with fertility rates in observa-tions by Vercellini et al [ 8 ] and Jones and Sutton [ 22 ] As the present study analyzes only the surgical outcome of total endometrioma excision, we were unable to make comparisons with other surgical techniques such as fenestration or ablation Favorable outcomes under laparoscopic cystectomy were reported by Alborzi et al [ 23 ] and Hart et al [ 24 ] Littman et al [ 25 ] declared a positive impact of laparoscopy for the treatment of endometriosis even after multiple in vitro fertilization failures

In contrast, other investigators [ 26 , 27 ] suggested that laparoscopic endometrioma excision has an adverse effect by reducing the ovarian reserve The present study indicates that there is a positive impact of additional medical treatment on postop-erative spontaneous pregnancy rate in line with previous observations [ 3 , 28 ] In contrast, other studies [ 29 , 30 ] observed a missing hormonal impact on the fertility rate after surgery [ 29 , 30 ] Further studies are necessary to determine the most effec-tive treatment of ovarian endometrioma

A limitation of this study is its study model, a retrospective cohort study, which has lower evidence and validity compared, for example, with a randomized con-trolled study The defi nition of recurrence varies in the literature Some studies defi ne recurrence as a typical morphological change represented in a vaginal ultra-sonogram, whereas others defi ne it as a recurrence or worsening view of subjec-tively perceived pain Although the general defi nition of a recurrent endometriosis remains to be determined, our defi nition represents a limitation because it is based

on a questionnaire We considered a positive response to the presence of a cyst or tumor in the questionnaire as a recurrence of endometriosis

Biases in this study include the alternating surgeon’s experience, the low return rate of questionnaires, and the development in hormonal treatment within the period

of data collection and observation (e.g., danazol, in spite of its interesting suppressive effects, is now not anymore very commonly applied, as drugs with less side effects like GnRh analogues and pure “gestagen” preparations, like Visanne, are on the market in most every country of the world) Among the strengths of the study are the long follow-up period, large sample size, and the fact that all patients were operated on in the same hospital

Conclusions

This study identifi es risk factors for recurrent ovarian endometrioma in our patient population as preoperative pain, preoperative dysmenorrhea, and larger cyst size Neither pain symptoms nor the risk of recurrence is included in the current endometriosis classifi cations However modifi ed classifi cations are on the way A classifi cation based on risk factors with high prognostic clinical outcome should allow an optimal individual therapy concept

The present study also indicates that patients with ovarian endometriomas and

a desire for pregnancy seem to profi t from additional postoperative medical

treatment For patients with completed family planning, the indication of additional postoperative medical treatment needs to be well evaluated according

to patients’ preferences As this article focuses only on endometriomas, we want

to add that the disease has, unfortunately, many other forms of expression that are not discussed in this paper

There are defi nitely ample opportunities to pursue research regarding the impact

of endometriosis in all its appearances as superfi cial, ovarian, deep infi ltrating, or distant endometriotic lesions across the lifespan of a female [ 7 ] It is necessary to follow the development of a number of therapeutical strategies that could plausibly

be expected to be both safe and benefi cial for women suffering with this systemic disease This is not an argument for taking our eye off the fact to fi nd endometriosis

as the primary disease, but rather we owe it to each of our patients to consider all

of the impacts at all times in life that this disease may incur [ 31 ]

3 Alkatout I, Mettler L, Beteta C et al (2013) Combined surgical and hormone therapy for metriosis is the most effective treatment: prospective, randomized, controlled trial J Minim Invasive Gynecol 20(4):473–481

4 Busacca M, Marana R, Caruana P et al (1999) Recurrence of ovarian endometrioma after roscopic excision Am J Obstet Gynecol 180(3 Pt l):519–523

5 Koga K, Takemura Y, Osuga Y et al (2006) Recurrence of ovarian endometrioma after scopic excision Hum Reprod 21(8):2171–2174

6 Kikuchi I, Takeuchi H, Kitade M, Shimanuki H, Kumakiri J, Kinoshita K (2006) Recurrence rate of endometriomas following a laparoscopic cystectomy Acta Obstet Gynecol Scand 85(9):1120–1124

7 Liu X, Yuan L, Shen F, Zhu Z, Jiang H, Guo SW (2007) Patterns of and risk factors for rence in women with ovarian endometriomas Obstet Gynecol 109(6):1411–1420

8 Vercellini P, Fedele L, Aimi G, De Giorgi O, Consonni D, Crosignani PG (2006) Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classifi cation system Hum Reprod 21(10):2679–2685

9 Fauconnier A, Chapron C, Dubuisson JB, Vieira M, Dousset B, Breart G (2002) Relation between pain symptoms and the anatomic location of deep infi ltrating endometriosis Fertil Steril 78(4):719–726

10 Kaya H, Sezik M, Ozkaya O, Sahiner H, Ozbaşar D (2005) Does the diameter of an trioma predict the extent of pelvic adhesions associated with endometriosis? J Reprod Med 50(3):198–202, Seproii Met

11 Busacca M, Chiaffarino F, Candiani M et al (2006) Determinants of long-term clinically detected recurrence rates of deep, ovarian, and pelvic endometriosis Am J Obstet Gynecol 195(2):426–432

12 Vercellini P, Barbara G, Abbiati A, Somigliana E, Vigano P, Fedele L (2009) Repetitive gery for recurrent symptomatic endometriosis: what to do? Eur J Obstet Gynecol Reprod Biol 146(1):15–21

sur-L Mettler and sur-L.V Maul

13 Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I (2008) Laparo-scopic surgery for triosis: how often do we need to re-operate? J Obstet Gynaecol 28(1):82–85, Surgical Therapy

endome-of Ovarian Endometrioma, Maul LV et al

14 Abbott JA, Hawe J, Clayton RD, Garry R (2003) The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2–5 year follow-up Hum Reprod 18(9):1922–1927

15 Renner SP, Rix S, Boosz A et al (2010) Preoperative pain and recurrence risk in patients with peritoneal endometriosis Gynecol Endocrinol 26(3):230–235

16 Busacca M, Fedele L, Bianchi S et al (1998) Surgical treatment of recurrent endometriosis: laparotomy versus laparoscopy Hum Reprod 13(8):2271–2274

17 Mettler L, Schollmeyer T, Lehmann-Willenbrock E et al (2003) Accuracy of laparoscopic diagnosis of endometriosis JSLS 7(1):15–18

18 Sesti F, Capozzolo T, PietropoUi A, Marziali M, BoUea MR, Piccione E (2009) Recurrence rate of endometrioma after laparoscopic cystectomy: a comparative randomized trial between post-operative hormonal suppression treatment or dietary therapy vs placebo Eur J Obstet Gynecol Reprod Biol 147(1):72–77

19 Bianchi S, Busacca M, Agnoli B, Candiani M, Calia C, Vignali M (1999) Effects of 3 month therapy with danazol after laparoscopic surgery for stage III/IV endometriosis: a randomized study Hum Reprod 14(5):1335–1337

20 Tsai YL, Hwang JL, Loo TC, Cheng WC, Chuang J, Seow KM (2004) Short-term tive GnRH analogue or danazol treatment after conservative surgery for stage III or IV endo- metriosis before ovarian stimulation: a prospective, randomized study J Reprod Med 49(12): 955–959

21 Yap C, Furness S, Farquhar C (2004) Pre and post operative medical therapy for endometriosis surgery Cochrane Database Syst Rev (3):CD003678

22 Jones KD, Sutton CJ (2002) Pregnancy rates following ablative laparoscopic surgery for metriomas Hum Reprod 17(3):782–785

23 Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zolghadri J, Alborzi S (2004) A spective, randomized study comparing laparoscopic ovarian cystectomy versus fenestration and coagulation in patients with endometriomas Fertil Steril 82(6):1633–1637

24 Hart RJ, Hickey M, Maouris P, Buckett W (2008) Excisional surgery versus ablative surgery for ovarian endometriomata Cochrane Database Syst Rev (2):CD004992

25 Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C (2005) Role of laparoscopic ment of endometriosis in patients with failed in vitro fertilization cycles Fertil Steril 84(6):1574–1578

26 Kuroda M, Kuroda K, Arakawa A et al (2012) Histological assessment of impact of ovarian endometrioma and laparoscopic cystectomy on ovarian reserve J Obstet Gynaecol Res 38(9):1187–1193

27 Esinler I, Bozdag G, Aybar F, Bayar U, Yarali H (2006) Outcome of in vitro cytoplasmic sperm injection after laparoscopic cystectomy for endometriomas Fertil Steril 85(6):1730–1735

28 Mettler L (1989) Pathogenesis, diagnosis and treatment of genital endometriosis Acta Obstet Gynecol Scand Suppl 150:31–37

29 Loverro G, Carriero C, Rossi AC, Putignano G, Nicolardi V, Selvaggi L (2008) A randomized study comparing triptorelin or expectant management following conservative laparoscopic surgery for symptomatic stage III-IV endometriosis Eur J Obstet Gynecol Reprod Biol 136(2):194–198

30 Busacca M, Somigliana E, Bianchi S et al (2001) Post-operative GnRH analogue ment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized controlled trial Hum Reprod 16(11):2399–2402, July–Sept 2014 Volume 18 Issue 3 e20l4.00223 8

31 Hughes CL, Foster WG, Aga S (2015) The impact of endometriosis across the lifespan of women: foreseeable research and therapeutic prospects BioMed Res Int 2015:158490

© International Society of Gynecological Endocrinology 2016

A.R Genazzani, B.C Tarlatzis (eds.), Frontiers in Gynecological Endocrinology:

Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities,

ISGE Series, DOI 10.1007/978-3-319-23865-4_16

Vitamin D Deficiency: Diagnosis,

Prevention, and Treatment – New

Vitamins D 2 and D 3 are available as dietary supplements and in various food items naturally or after fortifi cation [ 6 ]

16.3 Transport of Vitamin D, 25(OH)D and 1,25 (OH) 2 D

to the Tissues

Being synthesized in the skin by UV, vitamin D 3 enters the blood stream and is bound to vitamin D binding protein (VDBP) Vitamin D (D represents D 2 , or D 3 , or both) that is ingested in the gastrointestinal tract is incorporated into chylomicrons, which are absorbed into the lymphatic system and enter the venous blood Being transported to the liver, vitamin D is transformed to 25(OH) D, which is bound to VDBP and is secreted to the circulating blood However, vitamin D is also trans-ported to other tissues which, apart from 1-alpha hydroxylase, contain 25- hydroxylase converting vitamin D into 25(OH)D This local synthesis of 1,25 (OH) 2 D appears to fulfi ll autocrine functions [ 7 ] Independently from the above-mentioned intracellular transport system, there is also megalin-dependent endocy-tosis system [ 8 ]

25(OH)D requires a further hydroxylation in the kidneys by the αOHase (CYP27B1) to form the biologically active form of vitamin D 1,25(OH) 2 D [ 9 ] This system is also found in parathyroid glands and in the trophoblastic layer of placenta [ 7 10 ]

There are several other causes for vitamin D defi ciency [ 1 , 16 ] Patients with one

of the fat malabsorption syndromes and bariatric patients are often unable to absorb the fat-soluble vitamin D, and in patients with cholestasis, vitamin D emulsifi cation

by bile acid is impaired Severe hepatic parenchymal damage can results in 25(OH)

D defi ciency [ 17 ]

Patients with nephrotic syndrome lose 25(OH)D bound to the vitamin-D-binding protein in the urine Impaired 1α-hydroxylation is observed in chronic kidney dis-ease once creatinine clearance decreases to approximately 30–40 mL/min [ 1 17 ]

Epidemiological, genetic, and basic studies indicated a potential role of vitamin

D in the pathogenesis of certain systemic and organ-specifi c autoimmune diseases These studies demonstrate correlation between low vitamin D and prevalence of diseases There is a body of evidence regarding the plausible roles of vitamin D and VDR’s polymorphism in the pathogenesis of systemic (i.e., systemic lupus erythe-matosus, rheumatoid arthritis, psoriasis, etc.) and organ-specifi c (i.e., diabetes mel-litus, primary biliary cirrhosis, etc.) autoimmune diseases, in which low level of vitamin D was found compared to healthy subjects [ 18 ]

Low level of vitamin D is also found in cardiovascular diseases, i.e., lower serum

25 (OH) D levels are signifi cantly associated with impaired myocardial mance and LVMI [ 19 ] Hypertensive patients who were exposed to a tanning bed

Table 16.1 Pleiotropic actions of vitamin D [ 11 , 12 ]

Antiproteinuric effect Increased nephrin expression Suppression of renin, RR, AT II Decreased NF- κB activation Anti EGFR signaling?

Increased insulin sensitivity Increased glucose uptake Expression of insulin receptor Endothelial and cardiovascular protection Suppression of RAAS

Regulation of ANP Control of infl ammation Inhibition of smooth muscle cell proliferation

Regulation of apoptosis and antitumoral activity p21, p27

EGFR, TGF- α, C/EPB β Bcl2, Bax, caspase 3 Immunomodulation of lymphocytes,

macrophages and dendritic cells

Inhibition of Th1 cells Promotion of Th2 cells Induction of CD4 + CD25+ T cells Repression of γ-IFN, IL-2, GMCSF Promotion of Mycobacterium tuberculosis

secretion Control of muscle and neural function Muscle strength

Neural growth factor GDNF

16 Vitamin D Defi ciency: Diagnosis, Prevention, and Treatment – New Consensus

raised their blood concentrations of 25(OH)D by >180 % in 3 months and became normotensive [ 20 ] It was observed that in patients with low vitamin D concentra-tions, such disorders as ischemic heart disease, heart attack, stroke, cardiac arrhyth-mia, and hypertension were more frequent and mortality was signifi cantly higher [ 21 ] Vitamin D suffi ciency may also be an important protective factor for food allergy in the fi rst year of life [ 22 ] There is an inverse association of serum 25(OH)

D and body mass index (BMI) greater than 30 kg/m 2 , and thus, obesity is associated with vitamin D defi ciency [ 23 ] Low vitamin D level may be found in patients with colon cancer or prostate cancer [ 24 , 25 ]

16.6 Vitamin D Deficiency: Aging

Increased use of clothing and sunscreen over sun-exposed areas and decreased sumption of vitamin-D-fortifi ed milk increases the risk for vitamin D defi ciency In addition, age decreases the capacity of the skin to produce vitamin D 3 [ 1 ] Studies have revealed that aging does not alter the absorption of physiological or pharmaco-logical doses of vitamin D [ 26 ]

One of the studies on age and vitamin D conducted in Poland – the POLSENIOR study – showed negative correlation between serum vitamin D concentration and

biological age in elderly women ( r = − 0.2863, p = 0.001) [ 27 ]

16.7 Vitamin D Deficiency: Symptoms

Vitamin D defi ciency is often a silent disease In adults, vitamin D defi ciency results

in osteomalacia, which presents as a poorly mineralized skeletal matrix Adults in these cases can experience chronic muscle aches and bone pains

Other clinical symptoms suggesting vitamin D defi ciency include lack of tite, diarrhea, insomnia, vision disturbances, bad taste, and burning sensation in the oral cavity and throat [ 28 ]

appe-16.8 Vitamin D Deficiency: Diagnosis

Measurement of serum 25-hydroxyvitamin D (25[OH]D) is the best test to mine vitamin D status [ 29 ] Levels of 25(OH)D are interpreted as follows [ 30 ]: 30–100 ng/mL (75–250 nmol/L): Vitamin D suffi ciency

21–29 ng/mL (52.5–72.5 nmol/L): Vitamin D insuffi ciency

<20 ng/mL (<50 nmol/L): Vitamin D defi ciency

In Central Europe, levels of 25(OH)D are interpreted as follows [ 31 ]:

<20 ng/ml – Vitamin D defi ciency

16.9 Treatment for Vitamin D Deficiency

Recommended treatment for vitamin D defi ciency (vitamin D level below 20.0 ng/

ml = 50.0 nmol/l) comprises [ 31 ] the following:

Children and adolescent – from 3000 to 5000 IU/day

Adult – from 7000 to 10,000 IU/day

First control of 25OHD concentration is recommended after 3–4 months and then every 6 months Serum calcium, phosphate, and calcium in 24-h urine calcium measurement should be monitored every 1–3 months [ 32 ]

16.10 Prevention of Vitamin D Insufficiency

(Hypovitaminosis)

Prevention of hypovitaminosis D (serum 25OHD lower than 30.0 ng/ml) strategies comprises the following doses [ 30 ]:

Over 18 years old – 1500–2000 IU/day

Obese (BMI over 30.0 kg/m 2 ) – 4000 IU/day

Women planning pregnancy – 1500–2000 IU/day

Pregnant women over 18 years – from 1500 to 2000 IU/day (from at least second trimester)

Sever vitamin D defi ciency is defi ned as vitamin D concentration below 10 ng/ml

16 Vitamin D Defi ciency: Diagnosis, Prevention, and Treatment – New Consensus

Treatment dose suggested for fi rst 1–3 months is as follows:

for newborns, 1000 IU/day; infants, 1000–3000 IU/day; children, up to 5000 IU; and adults, up to 7000 IU [ 32 ]

Follow-up should be performed every 1–3 months and includes serum 25(OH)D concentration, alkaline phosphatase, calcium, phosphate, and 24-h urine calcium measurement with elaboration of creatinine index [ 32 ]

Useful calculations are as follows:

Vitamin D serum concentration: 1 ng/ml = 2.5 nmol/l 25(OH)D

Vitamin D dose: 40 IU = 1 μg vitamin D

16.12 Vitamin D Intoxication

The Drug and Therapeutics Committee of the Pediatric Endocrine Society took a systematic review of the safety of currently recommended high vitamin D doses as well as reported cases of intoxications in pediatrics [ 6 ]

Vitamin D hydroxylation to 25-hydroxyvitamin D (25OHD) in the liver depends

on substrate availability, and therefore, 25OHD concentrations rise in circulation during excess or intoxication In contrast, the subsequent 1 alpha-hydroxylation to 1,25-dihydrovitamin D 2 in the kidney is tightly regulated by PTH and under nega-tive feedback by calcium, phosphorus, and fi broblast growth factor 23 Consequently,

in vitamin D intoxication, serum 1,25-(OH) 2 D concentrations are usually normal

and do not correlate with serum calcium levels ( JCEM 2014) [ 6 ]

Both vitamins D 2 and D 3 are lipophilic and rapidly removed from the circulation

to various tissues such as adipose and muscle where they may remain stored for almost 2 months Their metabolite, 25OHD, has high affi nity for its transport pro-tein, vitamin D binding protein, which results in a long half-life of 2–3 weeks 25OHD is also lipophilic and can be stored in adipose tissue, remaining there for months Hence, vitamin D intoxication may take weeks to resolve and require pro-longed course of therapy [ 6 ]

1,25(OH) 2 D or Calcitriol is also available for the treatment for the hypocalcemia and secondary hyperparathyroidism of renal failure or rare conditions such as hypo-parathyroidism, pseudohypoparathyroidsm, or hypophosphatemic rickets Reports

on intoxication caused by excessive Calcitriol intake are extremely rare (relatively short biological half-life) [ 6 ]

During intoxication, high concentrations of 25OHD lead to hypercalcemia by increasing intestinal calcium absorption and bone resorption In turn, hypercalcemia increases the calcium load that is fi ltrated through the kidney, resulting in hypercal-ciuria via a mechanism that involves increased calcium excretion in the distal tubule Persistently elevated serum calcium levels may also cause polyuria and dehydration because of inability of the kidney to appropriately concentrate urine [ 6 ]

16.13 Causes of Vitamin D Intoxication

Vitamin-D-concentrated supplements use for veterinary purpose was mistaken as cooking oil The other cause may be excessive milk fortifi cation (70–600 times above state limit) In adults, cases of accidental or intentional intake of excessive vitamin D caused by a variety of circumstances such as misinterpretation of prescrip-tion instruction or inappropriate prescription of excessive vitamin D doses without monitoring 25OHD levels resulted in vague musculoskeletal complaints [ 6 ]

Both in the United States and in Europe, intoxications after manufacturing errors

of over-the-counter vitamin D formulations that contained substantially higher centrations than claimed on the label (production of such supplements is not over-seen be FDA ) were reported

Over one-half of over-the counter preparations and only one-third of the pounded pills met the US Pharmacopeial Convention Reference Standards contain-ing 90–110 % of the active ingredient, whereas the rest had either higher or lower concentrations than expected [ 6 ]

Bjelakovic et al assessed the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials The systematic review and meta-analysis comprised 68 randomized trials with 232,606 participants (385 pub-lications) It revealed that treatment with beta carotene, vitamin A, and vitamin E may increase mortality The authors concluded that the potential roles of vitamin C and selenium on mortality need further study [ 34 ]

Multivitamin preparations and dietary supplements are not recommended for min D defi ciency supplementation Multivitamin preparations, e.g., cod-liver oil, include various amounts of vitamin D and large amounts of vitamin A Ingestion of processed retinols may be toxic for the skeletal system and block vitamin D’s effects [ 35 ]

It should be remembered that vitamin D in the form of prescription drug enables strict control of the product (Table 16.2 )

Table 16.2 Notifi cation, modifi es

Prescription medicine Dietary supplement

Tests Necessity to carry out clinical

investigations

No obligation of investigations

Registration Registration of medicinal product

according to Pharmaceutical Law

Admission to turnover by Products

Registration Offi ce subordinate to

The Minister of Health

Notifi cation to Chief Sanitary

Inspector (Electronic System of

Notifi cation Message)

Safety Manufacturer carries out drug

qualitative and quantitative control

Manufacturer declares only quantitative amount of the component

Activity By defi nition, medicinal product:

prevents, treats, or modifi es organism

Cases of vitamin D dietary supplements intoxication reported in the literature are associated with doses other than those declared by the manufacturer For example,

a case report by Kaptein et al described two female patients with life-threatening hypercalcemia (refractory status epilepticus) [ 36 ] They had ingested vitamin D in dietary supplements Vitamin D content exceeded the amount presented in the leaf-let 100–1000 times Araki T et al presented two cases of patients with hypercalce-mia after intake of vitamin D supplements including the amount of this vitamin discrepant from the information in the leafl et Patients ingested vitamin D in doses 1000-fold exceeding daily needs [ 37 ]

In the last decade, a number of infants with suspected rickets who were scribed high vitamin D doses without prior measurement of 25OHD presented with severe life-threatening hypercalcemia Intoxication also occurred after intentional ingestion of products bought through the Internet for “good health” or dosing errors because of parental misinterpretation of the prescribed doses (400 IU/drop with

pre-400 IU/ml – an infant received a 30-fold over dose) [ 6 ]

16.14 Diagnosis of Vitamin D Intoxication

Hypercalcemia, poor appetite, weight loss, abdominal pain, vomiting, constipation, polyuria, polydipsia, and – in severe cases – life-threatening dehydration are symp-toms of vitamin D intoxication Vitamin D intoxication accounts for about 10 % of all cases of nephrocalcinosis [ 6 ] Diagnosis of vitamin D intoxication includes ele-vated serum 25OHD level (>150 ng/ml = 375 nmol/l), hypercalcemia, or hypercal-curia Serum 1,25 (OH) 2 D level is normal PTH is suppressed

In contrast, hypercalcemia and hypercalcuria, with normal serum 25OHD level, elevated 1,25 (OH) 2 D, and suppressed PTH, raise the suspicion of idiopathic intra-cranial hypertension In such cases, 24,25-dihydroxyvitamin D levels are low or undetectable [ 6 ]

16.15 Treatment of Vitamin D Intoxication

Treatment efforts in children and adolescents with symptomatic hypercalcemia get the source of vitamin D as a fi rst step It is removed, and the levels are allowed

tar-to decrease with time [ 6 ] The fi rst line therapy of hypercalcemia is iv hydration with normal saline to increase the glomerular fi ltration rate and calcium excretion

It can be combined with specifi c diuretics that increase calcium excretion, such as loop diuretics Furosemide at 1–2 mg/kg/day, as divided doses every 4–6 h, is usu-ally given Thiazides, on the other hand, should be avoided because they increase calcium reabsorption at the distal tubule and, therefore, can exacerbate hypercalce-mia [ 6] Glucocorticoids can be added if symptomatic hypercalcemia persists despite hydration and diuretics They prevent renal calcium reabsorption and inhibit the production and activity of 1,25(OH) 2 D and thus decrease intestinal calcium absorption Prednisone at 1–2 mg/kg/day or 20–25 mg/m 2 /day given as divided

kg every 6–12 h, because of the rapid effect on serum calcium As a last resort, hemodialysis can lower serum calcium rapidly and can be used in life-threatening cases, such as acute or chronic renal failure or hypercalcemic crisis [ 6 ]

16.16 Prevention of Vitamin D Intoxication

Health care providers should be aware of the various vitamin preparations and sel patients on both desirable doses and variability among formulations Empirical therapy of vitamin D defi ciency with high vitamin doses, such as stoss therapy, is discouraged without previous documentation of 25OHD concentrations and moni-toring serum 25OHD and calcium Health care providers should consider monitor-ing vitamin D levels in infants and children receiving treatment doses at the upper ranges currently recommended – the frequency, no more than every 6 months Vitamin D excess or intoxication should be included in the differential diagnosis in children who present with hypercalcemia or hypercalcuria Serum calcium concen-trations should be monitored in children with serum 25OHD levels above 150.0 ng/

coun-ml and measured by a reliable assay such as liquid chromatography tandem mass spectrometry For asymptomatic patients with vitamin D intoxication, monitoring of clinical symptoms, serum 25OHD, and calcium levels estimation until serum 25OHD values start declining is recommended [ 6 ]

References

1 Holick MF (2007) Vitamin d defi ciency N Engl J Med 357:266–281

2 Holick MF (2008) Vitamin D: a D-lightful health perspective Nutr Rev 66(10 Suppl 2): 182–194

3 Holick MF, Chen TC (2008) Vitamin d defi ciency: a worldwide problem with health quences Am J Clin Nutr 87:1080–1086

4 Holick MF, Chen TC, Sauter ER (2007) Vitamin D and skin physiology: a D-lightful story

J Bone Miner Res 22(Suppl 2):28–33

5 Moan J, Porojnicu AC, Dahlback A, Setlow RB (2008) Addressing the health benefi ts and risks, involving vitamin D or skin cancer, of increased sun exposure Proc Natl Acad Sci U S

A 105:668–673

6 Vogiatzi MG, Jacobson-Dickman E, DeBoer MD, Drugs, and Therapeutics Committee of The Pediatric Endocrine Society (2014) Vitamin D supplementation and risk of toxicity in pediat- rics: a review of current literature J Clin Endocrinol Metab 99(4):1132–1141

7 Segersten U, Hewisan M, Hellman P, Dralle H, Carling T et al (2002) 25-hydroxyvitamin D(3)- 1alpha-hydroxylase expression in normal and pathological parathyroid glands J Clin Endocrinol Metab 87:2967–2972

16 Vitamin D Defi ciency: Diagnosis, Prevention, and Treatment – New Consensus

8 Nykjaer A, Dragun D, Walther D et al (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D 3 Cell 96(4):507–515

9 DeLuca H (2004) Overview of general physiologic features and functions of vitamin D Am J Clin Nutr 80(6 Suppl):1689–1696

10 Tanaka Y, Halloran B, Schnoes HK, De Luca HF (1979) In vitro production of 1,25- dihydroxyvitamin D 3 by rat placental tissue Proc Natl Acad Sci U S A 76:5033–5035

11 Rojas-Rivera J, De La Piedra C, Ramos A, Ortiz A, Egido J (2010) The expanding spectrum

of biological actions of vitamin D Nephrol Dial Transplant 25:2850–2865

12 Liu PT, Stenger S, Li H et al (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response Science 311(5768):1770–1773

13 Zhou C, Assem M, Tay JC, Watkins PB, Blumberg B, Schuetz EG, Thummel KE (2006) Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia J Clin Invest 116:1703–1712

14 Adams JS, Hewison M (2006) Hypercalcemia caused by granulomaforming disorders In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn American Society for Bone and Mineral Research, Washington, DC, pp 200–202

15 Grey A, Lucas J, Horne A, Gamble G, Davidson JS, Reid IR (2005) Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insuffi ciency J Clin Endocrinol Metab 90:2122–2126

16 Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA (2008) Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared to 2000–2004 Am J Clin Nutr 88:1519–1527

17 Bringhurst FR, Demay MB, Kronenberg HM (2008) Hormones and disorders of mineral metabolism In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR (eds) Williams text- book of endocrinology, 11th edn Saunders Elsevier, Philadelphia, pp 1246–1247

18 Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y (2013) Vitamin D in systemic and organ- specifi c autoimmune diseases Clin Rev Allergy Immunol 45(2):256–266

19 Şeker T, Gür M, Uçar H, Türkoğlu C, Baykan AO, Özaltun B, Harbalıoğlu H, Yüksel Kalkan

G, Kaypaklı O, Kuloğlu O, Şen Ö, Koç M, Çaylı M (2014) Lower serum 25-hydroxyvitamin

D level is associated with impaired myocardial performance and left ventricle hypertrophy in newly diagnosed hypertensive patients Anadolu Kardiyol Derg doi: 10.5152/akd.2014.5637 [Epub ahead of print]

20 Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM (1998) Ultraviolet B and blood pressure Lancet 352(9129):709–710

21 Lavie CJ, Lee JH, Milani RV (2011) Vitamin D and cardiovascular disease will it live up to its hype? J Am Coll Cardiol 58(15):1547–1556

22 Allen KJ, Koplin JJ et al (2013) Vitamin D insuffi ciency is associated with challenge-proven food allergy in infants J Allergy Clin Immunol 131:1109–1116

23 Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity Am J Clin Nutr 72:690–693

24 Davis CD (2008) Vitamin D, and cancer: current dilemmas and future research needs Am J Clin Nutr 88(Suppl):565–569

25 Lin PH, Aronson W, Freedland SJ (2015) Nutrition, dietary interventions and prostate cancer: the latest evidence BMC Med 13:3

26 Harris SS, Dawson-Hughes B (2002) Plasma vitamin D and 25OH-D responses of young and old men to supplementation with vitamin D3 J Am Coll Nutr 21:357–362

27 Laczmanski L, Lwow F, Mossakowska M, Puzianowska-Kuznicka M, Szwed M et al (2015) Association between vitamin D concentration and levels of sex hormones in an eldery Polish population with different genotypes of VDR polymorphisms Gene 559(1):73–76

28 Holick MF (2003) Vitamin D, defi ciency: what a pain it is Mayo Clin Proc 78(12):1457–1459

29 Silverberg SJ, Fitzpatrick LA, Bilezikian JP (1996) The role of parathyroid hormone and min D in the pathogenesis of osteoporosis In: Marcus R, Feldman D, Kesley J (eds) Osteoporosis Academic, San Diego, pp 716–726

30 Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al (2011) Endocrine Society Evaluation, treatment, and prevention of vitamin D defi ciency: an Endocrine Society clinical practice guideline J Clin Endocrinol Metab 96:1911–1930

31 Pludowski P, Karczmarewicz E, Bayer M et al (2013) Practical guidelines for the tion of vitamin D and the treatment of defi cits in Central Europe—recommended vitamin D intakes in the general population and groups at risk of vitamin D defi ciency Pol J Endocrinol 64:319–327

32 Charzewska J et al (2010) Prophylaxis of vitamin D defi ciency – polish recommendation 2009 Pol J Endocrinol 61:228–232

33 Marcinkowska-Suchowierska E, Walicka M, Tałałaj M, Hosrt-Sikorska W et al (2010) Vitamin

D supplementation in adults – guidelines Pol J Endocrinol 61:723–729

34 Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis JAMA 297(8):842–857

35 Cannell JJ, Hollis W (2008) Use of vitamin D in clinical practice Altern Med Rev 13(1):6–20

36 Kaptein S, Risselada AJ, Boerma EC, Egbers PH, Nieboer P (2010) Life-threatening cations of vitamin D intoxication due to over-the-counter supplements Clin Toxicol (Phila) 48(5):460–462

37 Araki T, Holick MF, Alfonso BD, Charlap E et al (2011) Vitamin D intoxication with severe hypercalcemia due to manufacturing and labeling errors of two dietary supplements made in the United States J Clin Endocrinol Metab 96:3603–3608

16 Vitamin D Defi ciency: Diagnosis, Prevention, and Treatment – New Consensus

© International Society of Gynecological Endocrinology 2016

A.R Genazzani, B.C Tarlatzis (eds.), Frontiers in Gynecological Endocrinology:

Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities,

ISGE Series, DOI 10.1007/978-3-319-23865-4_17

A D Genazzani (*) • E Chierchia • G Despini • A Prati

Department of Obstetrics and Gynecology , Center for Gynecological Endocrinology,

University of Modena and Reggio Emilia , Modena , Italy

e-mail: algen@unimo.it

17

Medical Treatment of Myomas

Alessandro D Genazzani , Elisa Chierchia , Giulia Despini ,

and Alessia Prati

17.1 Introduction

Uterine fi broids or myomas are the most frequent benign neoplasm during fertile life in women It originates from the smooth muscle cells of the uterus (myome-trium) [ 1 ], and it is frequently found at a gynecological examination or at ultrasound

in almost 30 % of the women above 35 years of age Myomas are usually tomatic, but in 30 % of the women, they can induce a variety of symptoms such as dysmenorrhea, menorrhagia, pelvic discomfort, infertility, recurrent abortion, and when there several myomas and/or when they are quite large and heavy, they can induce diseases for the compression of the tissues and/or organs close to the uterus, such as the bladder [ 2 ]

Fibroids usually develop in the uterus, but they can develop almost in any other organ such as the intestine, the skin, and the vascular system (intravenous leiomyo-matosis) [ 2 ] According to the place where a myoma develops, the symptoms are different and variable, thus affecting the choice of treatment [ 3 ] In fact, fi broid location, size, and number infl uence signs and symptoms:

• Subserosal fi broids Fibroids that project to the outside of the uterus (subserosal

fi broids) can sometimes press on your bladder, causing you to experience urinary symptoms If fi broids bulge from the back of your uterus, they occasionally can press either on your rectum, causing a pressure sensation, or on your spinal nerves, causing backache

• Intramural fi broids Some fi broids grow within the muscular uterine wall

(intra-mural fi broids) If large enough, they can distort the shape of the uterus and cause prolonged, heavy periods, as well as pain and pressure [ 4 ]

• Submucosal fi broids Fibroids that grow into the inner cavity of the uterus

(sub-mucosal fi broids) are more likely to cause prolonged, heavy menstrual bleeding and are sometimes a problem for women attempting pregnancy They can be subdivided in types I and II according to the percentage (higher or lower than

50 %) of the fi broid located in the uterine cavity [ 5 ]

The common symptoms associated with uterine leiomyomas are irregular and/or excessive bleeding, which are the cause of anemia, pelvic pain, bowel and bladder dysfunction, and pain during sexual intercourse [ 2 6 ] On the basis of the severity

of such symptoms, uterine fi broids are the most common indication for tomy all over the world Although some medical treatments have been proposed, up

hysterec-to now, none of them has been reported hysterec-to be the perfect solution hysterec-to avoid the need

of surgery

17.2 Pathogenesis of Uterine Leiomyoma/Fibroid

Up to now, it is not clear why women develop uterine fi broids; nevertheless, there are specifi c racial differences since the prevalence of fi broids is over threefold higher in black women compared with white women [ 7 ] In addition, early men-arche, heredity, nulliparity, obesity, PCOS, diabetes, and others have been reported

to be major risk factors with the development of uterine fi broids [ 8 ]

According to recent studies, more than 50 % of the myomas have chromosomal abnormalities affecting various genes [ 6 ] In addition to genetic factors, recently, epigenetic mechanisms such as DNA methylation and histone modifi cation have been reported for myomas, thus supporting a high grade of gene deregulation com-pared to normal myometrium [ 6 9 ]

It is well known that estrogen and progesterone and their specifi c receptors have specifi c effects on myoma growth and that their actions are in part mediated by growth factors [ 6 , 8 , 10 ] such as EGF, platelet-derived growth factors (PDGF), TGF, IGF, VEGF, activin, myostatin, IL6, and other cytokines A specifi c key role is prob-ably played by extracellular matrix (ECM) components such as fi bronectin and pro-teoglycans [ 6 11 ], but the presence of estradiol and progesterone remains crucial Estradiol appears to be necessary to allow progesterone stimulatory action on fi broid growth, and both these gonadal steroids are necessary for the production of ECM components, such as collagen types I and II In fact, collagen fi bers are overex-pressed during the follicular phase of the cycle, and the P receptor antagonist aso-pristil down-regulates collagen fi ber synthesis in an in vitro model [ 11 ] The action

of estradiol in fi broid growth takes place through its receptor Erα Estradiol from the general circulation, as well as locally produced, is involved In fact, aromatase inhibitors are as effective as GnRH analogues in reducing fi broid volume with estra-diol concentrations remaining normal to high in aromatase inhibitor users and low

A.D Genazzani et al.

in GnRH analogue users [ 11 ] Part of estradiol action on myomas growth is ated through an IGF-1-stimulated production of the PCNA protein, which stimu-lates smooth muscle cells growth, and the BLC-2 protein, which inhibits apoptosis [ 12 ] (Fig 17.1 ) As additional confi rmation, cotreatment of GnRH analogue with progestins limited their therapeutic effi cacy, while this was not observed in women cotreated with estrogens and progestins [ 13 , 14] Finally, it has been reported recently that the use of selective progesterone receptor modulators (SPRMs) induces

medi-fi broid shrinkage similarly to that of GnRH analogue, maintaining normal estradiol plasma levels, thus confi rming the relevant role of P and P receptors (Pr) in fi broid growth [ 11 ]

17.3 Medical Treatment of Fibroids

The only treatment for fi broids that has been considered is myomectomy or ectomy or, in some cases, limited surgery such as myomectomy by hysteroscopy Although surgery remains as the unique remedy when bleeding is out of any con-trol, recently, new strategies have been developed to avoid hysterectomy, when possible

Medical treatment of fi broid is intended to relieve heavy menstrual bleeding to limit anemia and all the related side effects Unfortunately, at various levels, all these medical options induce anovulation and/or amenorrhea and, in several cases, have contraindications for pregnancy

Actually, the medical options available are progestins, SERMs, aromatase itors, GnRH analogues, and – the latest innovative remedy – SPRMs

Induction of EGF-R

in leiomyoma cells

Induction of EGF in leiomyoma cells Stimulation of EGF - EGF-R system

Leiomyoma cell growth

Inhibition of apoptosis

Induction of BCL-2

ProgesteroneEstrogen

?

PCNA protein

IGF-1

Estrogen

+

+ +

-+ +

Fig 17.1 Estrogen and progesterone modulation of fi broid growth

17.3.1 Progestins

For years, the use of oral or intramuscular progestins has been a classical treatment for abnormal dysfunctional bleeding (Table 17.1 ) since they act on the endome-trium, but no great advantages have been reported on fi broids [ 6 15 ] This is prob-ably due to the various characteristics of the progestins since some of them induce endometrial atrophy or suppress gonadotropin secretion However, progestins, as well as P, induce fi broids growth, as above discussed, although some of them show some benefi cial effects

One of the most used progestins is norethisterone acetate (NETA) NETA is a 19-nor-17α-ethynyltestosterone and has been demonstrated to modulate endome-trium growth, reducing menstrual bleeding and, to some extent, has been demon-strated to reduce fi broids size with no side effects both when used alone during the luteal phase of the menstrual cycle [ 16 ] and when combined with estrogens as hor-mone replacement therapy

Nomegestrol acetate (NOMAC), a 19-nor-progesterone derivative, has been demonstrated not to induce fi broid growth when coupled to estrogens both as con-traceptive pill and as hormonal replacement therapy [ 17 ], but no relevant clinical data have been produced on fi broid treatment Also danazol and levonorgestrel have been proposed to treat fi broids and with relatively good results [ 6 , 18 ] Recently, dienogest, a 19-nor-progesterone derivative, has been demonstrated to reduce leio-myomas growth and size in patients treated for endometriosis similarly to GnRH analogue [ 19 ] Although dienogest has indications for the treatment of endometrio-sis, it is able to reduce abundant menstrual bleeding induced by fi broids (especially

if intramural) since it acts specifi cally on the endometrium, inducing atresia

Table 17.1 Actual possible treatments for symptomatic uterine fi broids

Class Compound Effects on the patient Side effects

Progestins NETA

NOMAC Danazol LNG Dienogest LNG–IUD

Bleeding control Bleeding control Bleeding control Bleeding control Bleeding control Bleeding control SERMs Raloxifene Limited effi cacy Climateric symptoms Aromatase

inhibitors

Fibroid volume reduction Climateric symptoms

GnRH analogues Leupreline acetate Bleeding control, fi broid

volume reduction

Climateric symptoms, osteopenia

Ulipristal acetate Asoprisnil Telapristone acetate

Bleeding control Bleeding control, fi broid volume reduction Bleeding control Bleeding control, fi broid volume reduction

PAECs PAECs PAECs PAECs A.D Genazzani et al.