Hormone-dependent gynaecological disorders: a pathophysiological perspective for appropriate treatment

Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 22, No. 2, pp. 235–249, 2008 doi:10.1016/j.bpobgyn.2007.07.005 available online at http://www.sciencedirect.com

1 Hormone-dependent gynaecological disorders: a pathophysiological perspective for appropriate treatment Felice Petraglia *

MD

Professor Obstetrics and Gynecology

Concetta Musacchio

MD

PhD Student

Stefano Luisi

MD, PhD

Research Associate

Vincenzo De Leo

MD

Associate Professor Obstetrics and Gynaecology, Department of Paediatrics, Obstetrics and Reproductive Medicine, University of Siena Policlinico, S. Maria alle Scotte Viale Bracci, 53100 Siena, Italy

Hormonal changes are involved in several gynaecological disorders. Correct functioning of the hypothalamus–pituitary–ovarian (HPO) axis is critical for ovulatory function, as well as the growth and differentiation of uterine tissue (myometrium and endometrium). However, the correct functioning of other endocrine glands (thyroid, adrenal cortex, pancreas) is also crucial for correct reproductive function. Genes and environmental factors have an influence on women’s fertility through their effect on hormonal function. Consequently, dysfunction of the HPO axis and/or other endocrine systems may cause infertility and gynaecological disorders. The pathogenetic basis can be used to help make the correct clinical decision for treating these diseases. Disturbances related to the menstrual cycle, i.e. amenorrhoea, polycystic ovary syndrome (PCOS) and premenstrual syndrome (PMS), have a close correlation with hypo- or hypersecretion of hormones of the HPO axis. The roles of hypothalamic neurohormones and neurotransmitters in the various forms of amenorrhoea and PMS are well established. PCOS has a complex endocrine/metabolic origin, so a variety of hormonal treatments have been proposed. Hormone

* Corresponding author. Tel.: þ39 577 233 453; Fax: þ39 577 233 454. E-mail address: [email protected] (F. Petraglia). 1521-6934/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.

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derangement has also been proposed as the cause of endometriosis and uterine fibroids. These disorders do not have hyper- or hyposecretion of reproductive hormones, but hyperactivity of oestrogen receptors coupled with a genetic predisposition. The relevance of the endocrine changes is confirmed by the clinical effectiveness of hormonal treatments. In order to establish the correct treatment approach in gynaecological disorders, it is important to understand the endocrine pathophysiology. Key words: oestrogens; progesterone; gonadotrophins; prolactin; amenorrhoea; premenstrual syndrome; polycystic ovary syndrome; endometriosis; adenomyosis; uterine fibromatosis.

The hypothalamus–pituitary–ovary (HPO) axis is the key regulator of female reproductive function. Physiological and pathophysiological changes in reproductive organs and functions are under the control of neurohormones [gonadotrophin-releasing hormone (GnRH)], pituitary glycoproteins [follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL)] and sex steroid hormones (oestradiol, progesterone, androgens). Specific genes modulate their expression in endocrine glands as well as the expression of their receptors in reproductive organs. Disorders may derive from hyper- or hyposecretion of hormones or hyper- or hypo-activity of receptors. The most frequent disturbances related to the menstrual cycle are amenorrhoea, polycystic ovary syndrome (PCOS) and premenstrual syndrome (PMS). Endometriosis, adenomyosis and uterine fibromatosis are also related to endocrine derangement. AMENORRHOEA Amenorrhoea, or absence of menstrual cycles, is a symptom that characterizes the pathologies of various gynaecological, endocrinological, psychiatric, genetic, chromosomic and auto-immune conditions. In order to evaluate and treat amenorrhoea correctly, it is necessary to examine the association between amenorrhoea and other signs and/or symptoms and their physiopathological conditions. There are two major forms of amenorrhoea: primary, i.e. the presence of normal secondary sexual characteristics but no menarche by 16 years of age; and secondary, i.e. the absence of menses for 3 months in women with previously normal menstruation.1,2 In both primary and secondary amenorrhoea, the cause can be hypothalamic, pituitary, ovarian or uterine. Primary amenorrhoea Causes of primary amenorrhoea should be evaluated in the context of the presence or absence of secondary sexual characteristics (Figure 1). Presence of secondary sexual characteristics If secondary sexual characteristics have developed normally, it is necessary to evaluate the presence of malformations of the female genital tract, such as Rokitansky–Kuster– Hauser syndrome and congenital absence or abnormal development of the vagina. These are anomalies of Mullerian development that involve the lack or incomplete development of the uterus and the vagina, while the ovaries are normal. This explains the normal development of secondary sexual characteristics. In these cases, it is not necessary to give substitutive hormonal therapy because oestradiol and gonadotrophin

Hormone-dependent gynaecological disorders 237 Hypergonadotropic hypogonadism

Absence of secondary sexual characteristics

• Gonadal dysgenesis • Enzymatic deficits • Morris syndrome

• Constitutional delay of puberty Hypogonadotropic hypogonadism

• Systemic illness

Substitutive hormonal therapy

Follow-up

Causal therapy

Primary amenorrhoea • Kallmann syndrome

Presence of secondary sexual characteristics

Malformations of the female genital tract

• Substitutive hormonal therapy • Ovulation induction

Substitutive hormonal therapy

Figure 1. Evaluation of women with primary amenorrhoea.

levels are normal. The only treatment is surgical and consists of correction of the malformation. Absence of secondary sexual characteristics If primary amenorrhoea is associated with abnormal development or non-development of secondary sexual characteristics, it is necessary to consider hypergonadotropic (gonadal failure) or hypogonadotropic (hypothalamic-pituitary failure) hypogonadism. Hypergonadotropic hypogonadism. Hypergonadotropic hypogonadism in patients with primary amenorrhoea is frequently caused by gonadal dysgenesis, such as Turner’s syndrome (45,X0 karyotype), mosaicisms of X chromosome and pure gonadal dysgenesis with a XX karyotype.3 If primary amenorrhoea and hypergonadotropic hypogonadism are associated with hypertension and elevated serum levels of deoxycorticosterone, corticosterone and 18-hydroxycorticosterone, a deficiency in 17a-hydroxylase/ 17,20-lyase should be investigated. In this condition, adrenal and gonadal sex steroids are not produced. As a result, affected females are phenotypically normal but fail to undergo puberty.4 In these pathologies, primary gonadal failure and decreased or absent gonadal steroid secretion cause the absence of negative feedback and, in consequence, elevated serum LH and FSH. Therefore, these conditions require permanent substitutive hormonal therapy. Very rarely, primary amenorrhoea may be associated with elevated LH and normal FSH levels with incomplete or absent development of secondary sexual characteristics. This condition is known as ‘Morris syndrome’, characterized by an alteration in the X-linked recessive gene of the androgen receptor. The karyotype is 46 XY, the phenotype is feminine, the testes are ectopic and produce normal levels of testosterone, and the uterus and vagina are incompletely developed or absent. Management issues in syndromes of androgen insensitivity include decisions on sex assignment,

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timing of gonadectomy in relation to tumour risk, and genetic and psychological counselling. Substitutive hormonal therapy is indicated in this pathology.5 Hypogonadotropic hypogonadism. Hypogonadotropic hypogonadism is characterized by low serum oestradiol, FSH and LH levels and is caused by hypothalamic or pituitary failure. The most common cause of hypogonadotropic hypogonadism in primary amenorrhoea is constitutional delay of growth and puberty. It is a familiar condition that does not require intervention, because secondary sexual characteristics develop and menarche occurs at a later age than usual. Kallmann syndrome is a congenital disorder that causes hypogonadotropic hypogonadism. This pathology consists of GnRH deficiency associated with hyposmia and hypoplasia of the olfactory lobes, and it is due to the failure of fetal GnRH neurosecretory neurones to migrate from the olfactory placode to the medial basal hypothalamus. About half of all cases with Kallmann syndrome have mutations in the KAL gene on chromosome Xp22.3, which encodes an extracellular matrix protein that appears to regulate cellular adhesion. Recently, mutations in the fibroblast growth factor receptor 1 gene were found in Kallmann syndrome with an autosomal mode of inheritance.6 In these subjects, the ovaries are small but they are able to produce hormones if stimulated correctly. As such, substitutive hormonal treatment can be used to obtain good sexual development and regular menstrual cycles, and finally induction of ovulation by GnRH or gonadotrophins. Gene therapy could be available in the future.6 Other causes of primary amenorrhoea associated with hypogonadotropic hypogonadism are chronic illnesses such as chronic renal insufficiency, leukaemia and malnutrition. In these conditions, cause-specific treatment should be used rather than substitutive hormonal therapy.7 Secondary amenorrhoea In secondary amenorrhoea, the examination of associated signs and symptoms is also critical for diagnosis and therapeutic evaluation (Figure 2). Hypothalamic failure Hypothalamic amenorrhoea is a common cause of amenorrhoea and is due to a dysfunction of hypothalamic signals to the pituitary gland. It can have organic (central nervous system tumour, chronic illness) or functional (excessive weight loss, intense exercise, stress) causes. If secondary amenorrhoea is associated with a distorted body image, obsessive fear of obesity, food avoidance and excessive weight loss, anorexia nervosa should be considered. In this case, amenorrhoea is associated with a marked reduction in gonadotrophin secretion to a level comparable with prepubertal girls. The underlying cause of this hypogonadotropic state is the reduced frequency and amplitude of LH pulsatile release due to the arrest of hypothalamic GnRH pulsatile activity. Oestradiol secretion is low, while the hypothalamic corticotrophin-releasing hormone (CRH)–adrenocorticotrophic hormone–adrenal axis is activated by hypersecretion of cortisol. CRH inhibits hypothalamic GnRH secretion, and glucocorticoids inhibit pituitary LH and ovarian oestrogen and progesterone secretion. Insulin sensitivity is increased, glucose effectiveness is reduced and fasting plasma glucose and insulin levels are low. Serum T4 and T3 levels and leptin (an adipocyte hormone that represents the linkage between energy stores and reproduction) are lower in these patients than in healthy women.

Hormone-dependent gynaecological disorders 239 • Moderation of exercise • Nutritional modification • Hormonal therapy for bone demineralization

Intense physical exercise Excessive weight loss

• Psycho-analysis • Family therapy • Force feeding

Anorexia nervosa

• Headache • Emianopia • PRL>100 ng/mL Secondary amenorrhoea

• Hyperprolactinaemia • Galactorrhoea (30–50%)

Hypothyroidism Antidopaminergic drugs

FSH>40 mUi/mL

POF

• Hyperandrogenism • Anovulatory infertility

PCOS

Pituitary adenomas

• Dopaminergic drugs • Surgical treatment

Hormonal therapy (T4) Suspension of drug

Substitutive hormonal therapy Specific therapy

Figure 2. Evaluation of women with secondary amenorrhoea. PRL, prolactin; FSH, follicle-stimulating hormone; POF, premature ovarian failure; PCOS, polycystic ovary syndrome.

Recently, other factors such as neuropeptide Y, cytokines [tumour necrosis factora (TNF-a)] and urocortin (CRF-related peptide) have been shown to influence the relationship between energy status and reproduction.8,9 All these hormonal alterations are normalized by weight gain, suggesting that the cessation of reproductive function in this syndrome may be viewed as a protective strategy in the face of severe nutritional deficit, and that a critical amount of body fat is essential to achieve and maintain normal reproductive function.10 In these patients, therapeutic interventions have included psycho-analysis, family therapy, force feeding and behavioural modification. Excessive weight loss and stress also induce secondary amenorrhoea associated with intense physical exercise. This is common in athletes. Low energy availability alters LH pulsatility in exercising women and induces the same endocrine and metabolic alterations found in anorexia nervosa.11 Moderation of exercise and establishment of optimal nutritional needs are the best treatment for these patients. Supplementation with oestrogen/progestin may be proposed to minimize bone demineralization in amenorrhoeic adolescents. Pituitary failure If secondary amenorrhoea is associated with galactorrhoea, hyperprolactinaemia may be suggested. This condition has many causes; some reflect pathological processes (hypothalamic lesions, pituitary tumours, chronic renal failure) and others are consequences of reversible functional disorders (hypothyroidism, pharmacological causes). In all these conditions, supraphysiological concentrations of PRL exert an inhibitory

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effect on the HPO axis. Evidence suggests that hyperprolactinaemia inhibits GnRH activity by interacting with the hypothalamic dopamine and opioidergic systems through the short-loop feedback mechanism or by a direct effect on GnRH neurones.12,13 When PRL levels are very high, and headache and bitemporal hemianopia are detected, the most probable diagnosis is a pituitary adenoma. These tumours are arbitrarily classified by size into micro-adenomas (1 cm), the latter being associated with greater elevations of PRL. In both, the most common form of treatment is a dopamine agonist to reduce the size of the tumour and lower PRL levels. In cases resistant to therapy, a trans-sphenoidal resection of PRL-secreting adenoma is suggested. The presence of hypothyroidism should be evaluated, as a decrease in T3 and T4 may induce an increase in thyrotrophin-releasing hormone secretion, enhancing PRL and thyroid-stimulating hormone release. In this condition, replacement of thyroid hormone can resolve amenorrhoea associated with hyperprolactinaemia. Also, some drugs may increase the level of PRL such as antipsychotics, antidepressants, antihypertensives, histamine H2 blockers and opiates. These drugs interfere with synthesis, metabolism, re-uptake and/or receptor binding of dopamine, thus reducing dopamine availability and resulting in hyperprolactinaemia. Suspension of these drugs restores the menstrual cycle. Ovarian failure Amenorrhoea associated with premature ovarian failure (POF) is due to cessation of ovarian function before the age of 40 years, and is characterized by elevated FSH levels in the menopausal range on at least two occasions.14 In this condition, menopausal symptoms may be associated with secondary amenorrhoea, i.e. hot flushes, irritability, insomnia and vaginal dryness. A wide spectrum of pathogenic mechanisms may lead to the development of POF, including chromosomal, genetic, auto-immune, metabolic and iatrogenic (anticancer treatments) causes. In a large proportion of cases, no cause is found and they are classified as idiopathic.15 In particular, X chromosome abnormalities range from a numerical defect such as complete deletion of one X (Turner’s syndrome) and trisomy X, to partial defects in the form of deletions and balanced X autosome translocations.16 A ‘critical region’ for normal ovarian function has therefore been proposed for Xq13–q26. Within this region, the most frequent breakpoints involve two specific regions defined as POF loci: POF1 and POF2.16 On the other hand, autosomal abnormalities have been identified in POF patients such as mutations of the phosphomannomutase 2 gene, the FSH receptor gene and the galactose-1-phosphate uridyltransferase gene.16 In addition, inhibin, a glycoprotein that inhibits synthesis and secretion of pituitary FSH, has been considered as a strong candidate gene in the aetiology of POF. The presence of low serum inhibin levels in POF further supports its role in the pathophysiology of POF.17 In POF, the hormone defect may be treated with oestrogen/progestin preparations to relieve menopausal symptoms and to prevent long-term health sequelae of oestrogen deficiency, such as osteoporosis. POLYCYSTIC OVARY SYNDROME PCOS is a complex and heterogeneous syndrome that can be characterized by oligoamenorrhoea, anovulatory infertility, clinical and/or biochemical signs of hyperandrogenism, overweight or obesity, and insulin resistance.18 The pathophysiollogical

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mechanisms that determine the manifestation of PCOS are complex and are due to interaction between various genetic, endocrine and environmental factors.19 Consequently, there are various treatments for these patients (Figure 3). Oligoamenorrhoea and anovulatory infertility are due to alterations in follicologenesis typical of PCOS that are caused by several pathogenetic mechanisms: dysregulation of GnRH pulse generator; ovarian and adrenal hyperandrogenism; insulin resistance; and alterations in ovarian growth factors.18 In women with PCOS, 55–75% have a high LH:FSH ratio; this is primarily due to increased levels of LH rather than low levels of FSH.20 GnRH stimulation and gonadotrophin pulsatility tests indicate hyperactivity of the hypothalamo-pituitary axis.21 It is not yet clear whether altered hypothalamo-pituitary function is an intrinsic factor in PCOS or secondary to steroid hormone anomalies. Hyperandrogenaemia is a key feature of PCOS. It is mainly of ovarian origin, although an adrenal contribution cannot be excluded. Acute administration of GnRH or human chorionic gonadotrophin is followed by greater 17-hydroxyprogesterone (17OHP) production than in normal women.22,23 This and other observations have led to the hypothesis that 17-hydroxylase and 17,20-lyase activities, constituents of the enzyme P450c17, are altered in PCOS. The consequence of the intrinsic dysregulation of this enzyme is a relative inhibition of 17,20-lyase with respect to 17-hydroxylase, and thus an increase in 17OHP compared with normal women. Clinically, hyperandrogenaemia may induce acne and hirsutism, which are treated with antiandrogen drugs that bind to androgen receptors.24 In addition, contraceptives may reduce acne and hirsutism and improve menstrual cycles in PCOS women.25 It has been proposed that hyperinsulinaemia plays a role in ovarian and adrenal steroidogenesis in PCOS women. Approximately 60–70% of PCOS patients are obese and it is well known that obesity is associated with insulin resistance. However, insulin resistance is also found in normal-weight women with PCOS.26 Insulin resistance could be due to a defect in insulin binding to its receptor or a post-binding defect in insulin action.27 However, the ovaries of an insulin-resistant subject remained sensitive to hyperinsulinaemia. A hypothesis for this is that insulin acted via insulin-like

Anti-androgens ± insulin-sensitizing drug Acne Hirsutism

Ovarian and adrenal hyperandrogenism

Contraceptives with anti-androgenic progestin ± insulin-sensitizing drug

Dysregulation of GnRH pulse generator PCOS

Oligoamenorrhoea Anovulatory infertility

Hyperandrogenism

Insulin resistance

Obesity Overweight

Improvement of menstrual cycles (oral contraceptives, insulin-sensitizing drug)

Insulin resistance

Ovulation induction (insulin sensitizing drug, clomiphene, gonadotrophins)

Weight loss, physical exercise Insulin-sensitizing drug

Figure 3. Evaluation of women with polycystic ovary syndrome. GnRH, gonadotrophin-hormone releasing hormone; PCOS, polycystic ovary syndrome.

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growth factor-I (IGF-I) receptors, which only bind at high concentrations such as in insulin resistance and hyperinsulinaemia. Moreover, it has been shown that the action of insulin on the ovaries is mediated by inositolglycan mediators, and is therefore distinct from the insulin-activated tyrosine phosphate cascade that enhances glucose utilization.28 This indicates that the induction pathways of insulin signalling are also separate in the ovaries, and that the action of insulin on steroidogenesis is even maintained in cases of insulin resistance. Insulin stimulates ovarian steroidogenesis by granulosa and thecal cells. By stimulating the proliferation of thecal cells, insulin increases LH-stimulated androgen secretion, increases P450c17 mRNA levels, upregulates LH receptors and upregulates ovarian IGF-I receptors.29,30 Since the key enzyme of androgen synthesis, P450c17, is expressed in the gonads and adrenals, various studies have demonstrated that adrenal hyperandrogenism is secondary to hyperinsulinaemia.30,31 Finally, insulin regulates androgen metabolism by affecting synthesis and secretion, and indirectly by regulating circulating levels of sex hormone binding globulin, which has high affinity for sex hormones. Insulin also inhibits liver production of IGF binding protein-1 (IGFBP-1), which leads to an increase in the free fraction of IGF-I. Several studies have found a significant increase in the IGF-I:IGFBP-1 ratio in women with PCOS.32 As a consequence, increased bioavailability of IGF-I to thecal tissue may have a co-gonadotrophin role, inducing hyperandrogenism by autocrine and paracrine mechanisms. In the PCOS insulin-resistant women insulin-lowering drug have been effective on insulin resistance, weight loss, anovulatory cycles and hirsutism27, also in combination with gonadotropin treatment33, or with oral contraceptive.25 Some women with PCOS have elevated PRL levels due to persistently elevated oestradiol levels typical of PCOS. Dopaminergic drugs are utilized in addition to other treatments. PREMENSTRUAL SYNDROME PMS is a collection of affective, behavioural and somatic disorders that occur in a cyclic pattern during the second half of the menstrual cycle. The symptoms include breast tenderness, abdominal bloating, oedema of the lower extremities, fatigue, mood swings, depression and headache. Numerous hypotheses have been proposed, but the underlying physiopathological cause of PMS remains to be identified. The behavioural symptoms of PMS are likely to be linked to responses of target cells in the brain to ovarian factors. It has been suggested that changes in either oestradiol or progesterone during the follicular and periovulatory phases may be crucial in the onset of symptoms in the luteal phase.34 In particular, increased severity of PMS symptoms has been shown to be associated with significantly increased levels of oestradiol and decreased levels of progesterone in the luteal phase. However, data confirming the participation of permanent hormonal disturbances in PMS are lacking, and the level of progesterone is not always changed in women suffering from PMS.35,36 Recently, it has been shown that low levels of neuroactive progesterone metabolites in the central nervous system, such as 3-alpha-hydroxy-5-alpha-dihydroprogesterone and 3-alpha alphatetrahydrodeoxy corticosteron, are correlated with the incidence of PMS.37,38 These compounds reveal anxiolytic, analgesic and anaesthetic properties, and they interact with GABA receptors. Consequently, in some PMS patients, the administration of GABAergic drugs, such as alprazolam, may lead to symptom improvement. However, there is abundant evidence indicating that behavioural symptoms of PMS are partially associated with disturbed serotoninergic conductivity.39

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In some women suffering from PMS, serotoninergic agonists are effective in alleviating irritability, depression and anxiety. A significant role of PRL has been postulated in the aetiology of breast tenderness manifested by an altered 24-h secretion profile with a significant nocturnal increase in PRL observed in about 70% of women suffering from PMS.40 Consequently, dopaminergic drugs have been proposed to treat PMS patients with breast tenderness. It is believed that altered aldosterone activity, leading to sodium and water retention, may explain abdominal bloating and oedema of the lower extremities in PMS. When these symptoms are particularly strong, spironolactone or other diuretics can be used. Finally, dietary deficits in calcium, magnesium and pyridoxine may be risk factors for PMS. Dietary supplementation and changes in diet have been shown to have beneficial effects.41 Non-pharmacological measures (regular physical activity, relaxation techniques) for 2–3 months can ameliorate PMS symptoms or eradicate them completely.41 ENDOMETRIOSIS Endometriosis is one of the most common benign gynaecological conditions. It is characterized by the presence and proliferation of endometrial tissue outside the uterine cavity.42,43 It is an oestrogen-dependent disease that causes pelvic pain in women of reproductive age, and has a dramatic impact on women’s professional, social and marital lives. The glands and stroma of endometriosis are usually responsive to gonadal hormones, although steroid receptor levels are somewhat lower than those in normal endometrium. Biochemical changes in ectopic endometrium mimic those of the uterine cavity in response to the late luteal-phase decline in progesterone, including increased production of prostanoids that promote inflammation, fibrosis and adhesion formation. Studies have indicated that nulliparous women and women reporting short and heavy menstrual cycles are at increased risk of developing endometriosis. The primary symptoms of endometriosis include chronic pelvic pain, dysmenorrhoea and dyspareunia. Endometriosis is also the primary cause of infertility (rate 20–50%)44 (Table 1). The secondary symptoms are shown in Table 2. Different pathogeneses have been suggested to explain the different clinical entities of endometriosis: metaplasia of mesothelium (ovarian endometriosis); in-situ Table 1. Primary symptoms and causes of women with endometriosis, adenomyosis and fibromatosis. Endometriosis

Pelvic pain Dysmenorrhoea Dyspareunia Infertility

Metaplasia of mesothelium Development of Mullerian remnants in the recto-vaginal septum Retrograde transplantation of shed menstrual effluent

Adenomyosis

Pelvic pain Dysmenorrhoea Metrorrhagia

Originates from the deep part of the endometrial mucosa Intramyometrial lymphatic system diffusion Metaplasia from de-novo ectopic intramyometrial endometrial tissue

Infertility Fibromatosis

Pelvic pain Metrorrhagia Infertility

Actions of steroid hormones Genetic alterations in the leiomyoma cells Possibly abnormal celleextracellular matrix interactions

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Table 2. Secondary symptoms of endometriosis. Deeply infiltrating endometriosis

Constipation Diarrhoea Painful defaecation Intestinal subocclusion

Ureteral endometriosis

Dysuria Haematuria Pollakiuria Non-microbial cystitis Recurrent urinary tract infections

development of Mullerian remnants in the recto-vaginal septum (deep endometriosis); and retrograde transplantation of shed menstrual effluent (peritoneal implants). Endometriosis is considered to have a hormonal pathology (oestrogen and progesterone), with the respective receptors regulating the growth of eutopic and ectopic endometrial tissue.45 Endometrial cells produce oestrogen via local action of aromatase, which is also present in ectopic lesions. Endometriotic lesions show increased biosynthesis and decreased oestradiol inactivation compared with endometrium in healthy women. In endometriotic tissue, the production of prostaglandin E2 (aromatase stimulator) is increased, with subsequent positive feedback that favours the continued production of oestradiol. Progesterone induces secretive differentiation and endometrial decidualization, and reduces expression of the genes of the metalloprotease family that attack extracellular matrix and favour ectopic lesions. According to the transplantation theory of endometriosis, when shed endometrium is placed in the peritoneal cavity, establishment of a new blood supply is essential for survival of the implant and development of endometriosis. Angiogenesis includes proliferation, migration and extension of endothelial cells, adherence of these cells to the extracellular matrix, remodelling of this matrix, and formation of a lumen. Several angiogenic factors (i.e. factors that aid in the development of new blood vessels) are expressed by endometrium and endometriosis.46 The most studied of these factors is vascular endothelial growth factor, which is responsible for the induction of early vascular growth. This molecule is expressed and secreted by endometriosis lesions, endometriomas and in the peritoneal fluid of women with endometriosis.47 Peritoneal TNF-a levels in women with endometriosis are higher than those in healthy women. TNF-a can stimulate endometrial adhesion and proliferation, and expression of matrix metalloproteinases (MMPs) . It can also stimulate angiogenesis through expression of interleukin-8.48 Medical therapy of endometriosis is based on the concept that ectopic endometrium is modulated by sex hormones. Classic strategies are: creation of a hypo-oestrogenic hormonal climate in order to reduce the trophism of endometriotic lesions; and creation of pseudodecidualization via oestroprogestinic treatments. Another therapeutic approach is reduction of inflammation and pain with anti-inflammatory drugs. The medical treatment of endometriosis has long centred upon producing a hypooestrogenic environment through pituitary suppression or a progestin-dominant environment. Current research has focused on medications designed to attack specific aspects of the development and maintenance of endometriosis.

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ADENOMYOSIS Adenomyosis is defined as the intramyometrial presence of endometrial mucosa (glands and stroma) surrounded by reactive, hypertrophic myometrium. Adenomyosis causes globular and cystic enlargement of the myometrium with some cysts filled with extravasated, often haemolysed red blood cells and siderophages.49 Adenomyosis is a poorly understood condition that has been called ‘elusive’ or ‘enigmatic’ because of diagnostic difficulties, the lack of agreement on definition, and the vague and ill-defined symptoms. There is little doubt that some women with adenomyosis experience troublesome, heavy menstrual bleeding, troublesome dysmenorrhoea and a tender uterus. The common association of adenomyosis with other pelvic pathologies is an additional factor that confuses the understanding of related symptoms. It is clear that there is no specific combination of symptoms caused by adenomyosis, although many women undoubtedly suffer from very heavy menstrual periods50 (Table 1). The cause(s) and mechanisms of development of intramyometrial endometrium are not clear. Three theories have been proposed, but consensus has yet to be reached. The first hypothesis is that adenomyosis originates from the deep part (basalis) of the endometrial mucosa. The latter invaginates between bundles of smooth muscle fibres of the myometrium, possibly due to loss of tissue cohesion caused by specific enzymes.51,52 This situation enhances endometrial invagination of either a structurally weakened myometrium or by the influence of ovarian hormones via their respective sex-steroid receptors. Oestradiol receptor expression in the adenomyotic foci is greater than in the normal endometrium and is associated with expression of the apoptosis-suppressing gene product, bcl-2, throughout the menstrual cycle.53 The second theory suggests that invagination of the basalis proceeds along the intramyometrial lymphatic system. Adenomyosis can be found in hysterectomy specimens within intramyometrial lymphatics.54 According to the third theory, adenomyosis may originate and ultimately develop through metaplasia from de-novo ectopic intramyometrial endometrial tissue. The endometrium and subjacent myometrium have a common embryological origin (Mullerian ducts).55 Dysmenorrhoea may be due to uterine irritability secondary to increased blood loss or intramyometrial pressure due to the accumulation of menstrual blood within foci of adenomyosis.56 UTERINE FIBROMATOSIS Uterine fibromatosis are the most common benign gynaecological tumours. In general, incidence and size increases with age.57 Heredity probably plays an important role; if a mother or sister had fibroids, there is increased risk. Fibroids may cause pain and menstrual bleeding to the point of anaemia. Fibroid location influences signs and symptoms. Fibroids that grow into the inner cavity of the uterus (submucosal fibroids) are thought to be primarily responsible for prolonged, heavy menstrual bleeding. Fibroids that project to the outside of the uterus (subserosal fibroids) can press on the bladder or ureter, causing urinary symptoms. Fibroids clearly reduce fertility, increase preterm labour and delivery, and markedly increase the risk for caesarean delivery58–60 (Table 1). The pathogenesis of uterine fibroids appears to be rooted in the actions of steroid hormones, genetic alterations in leiomyoma cells, and possibly abnormal cell–extracellular matrix interactions. Traditionally, oestrogen has been proposed as the primary promoter of uterine leiomyoma growth. This supposition has been based in part

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upon the clinical observations that fibroids only occur after menarche, develop during the reproductive years, may enlarge during pregnancy, and frequently regress following menopause. Furthermore, as the risk of fibroids is greater in nulliparous women who may be subject to a higher frequency of anovulatory cycles and obese women with greater aromatization of androgens to oestrone in the fat, the concept of unopposed oestrogen as an underlying cause of uterine fibroids has been proposed in the literature.61–63 The oestrogen hypothesis has also been supported by clinical trials evaluating the medical treatment of myomas with GnRH agonists, the effective result of which is hypo-oestrogenism accompanied by regression of the fibroids.64 Indeed, clinical and laboratory evidence to date appears to indicate that oestrogen and progesterone may both be important as promoters of myoma growth.61 We can consider the impact of sex steroid upon fibroid growth in two clinical situation: pregnancy and medical treatment with GnRH agonists.65–67 Transforming growth factor-b3 (TGF-b3) and basic fibroblast growth factor (bFGF) may be critical in the pathogenesis of fibroids in view of their combined mitogenic effect and promotion of extracellular matrix production.68 Epidermal growth factor appears to be significant, as it is the only characterized growth factor, other than TGF-b3, with elevated expression during the luteal phase, when leiomyoma mitotic activity is maximal. IGF-I almost certainly plays an important role because of its potent mitogenic capacity and the overexpression of both the peptide and its receptor in leiomyomas. Practice points  functional hypothalamic amenorrhoea syndromes are the most common clinical disorders. Both psychogenic, exercise-related and nutritional deficits share multiple neuro-endocrine-metabolic derangements  the physiopathological mechanisms that determine the manifestation of PCOS are complex and are due to interactions between various genetic, endocrine and metabolic factors; the long-term sequelae of PCOS include the development of endometrial cancer, type 2 diabetes and cardiovascular abnormalities  PMS is associated with affective disorders, and mounting evidence supports the impact of cyclic ovarian steroids on serotoninergic neurotransmission in the manifestation of symptoms  biochemical activity in ectopic endometrium (endometriosis/adenomyosis) renders this tissue sensitive to hormonal treatments, both in term of pseudopregnancy or iatrogenic menopause

Research agenda  genome-wide linkage studies are currently ongoing in women with POF, PCOS, endometriosis and uterine fibroids. The single nucleotide polymorphism (SNP) association studies are becoming available, allowing for entirely novel approaches in the unravelling of currently unknown genes involved in complex conditions  to evaluate simultaneous changes in the genome, transcriptome (mRNA), proteome (proteins) and metabolone (metabolites) in women with endometriosis or uterine fibroids in order to develop new diagnostic or therapeutic tools

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