Reproductive System Disorders

1. Reproductive System Disorders Mehtap KAÇAR KOÇAK MD. PhD Yeditepe University, Medicine School

2. Overview • A- Alterations of sexual maturation: • Delayed Puberty • Precocious puberty • B- Disorders of male reproductive system: • Male Infertility • Prostatitis • Benign Prostatic Hypertrophy • Prostate Cancer • C- Disorders of female reproductive system: • Female Infertility • Disorders of Menstruation • Endometriosis • Pelvic Inflammatory Disease • Ovarian Cysts • Breast Diseases • Cancers of female reproductive system

3. Puberty and its disorders

4. Puberty • Puberty is a stage of human development when sexual maturationand growth are completed and result in ability to reproduce. In puberty; - Accelerated somatic growth - Maturation of primary sexual characteristics (gonads and genitals) - Appearance of secondary sexual characteristics (pubic and axillary hair, female breast development, male voice changes,...) - Menstruation and spermatogenesis begin

5. Puberty – hormonal changes Hormonal changes procede physical changes Increased stimulation of hypothalamo-pituitary-gonadal axis • gradual activation of the GnRH (LHRH) • increases frequency and amplitude of LH pulses. • gonadotropins stimulate secretion of sexual steroids (estrogenes and androgenes) • extragonadal hormonal changes (elevation of IGF-I, and adrenal steroids)

6. The first sign of puberty are: • thelarche in girls • Enlargement of testes and scrotal thinning in boys

7. Pubertal disorders: A. Precoccious puberty B. Delayed puberty

8. Precocious puberty PP is defined as a sexual maturation before age of 6 in black girls before age of 7 in white girls before age of 9 in boys. PP occurs in many forms, including isosexual, heterosexsual, and incomplete.

9. Isosexual PP: • premature development of appropiate characteristics for the child’s sex, • Hypothalamic-pituitary-ovarian axis working normally but prematurely • in about 10% of cases, lethal nervous system tumor may be cause.

11. Central (true), gonadotropin-dependent Early stimulation of hypothalamic-pituitary-gonadal axis. Periferal, GnRH independent (precocious pseudopuberty) The source of sex steroid may be endogenous or exogenous, gonadal or extragonadal, independent of gonadotropins stimulation.

12. True precocious puberty(central, gonadotropin-dependent) Always isosexual! Bone age is accelerated FSH and LH elevation after LH-RH is diagnostic test (LH/FSH > 2) MRI of CNS is necessary to exclude the neoplasia

13. Heterosexual PP: • It causes the child to develop some secondary sex characteristics of the opposite sex, • Common causes: • adrenal hyperplasia or androgen-secreting tumors…

15. Heterosexual pubertal development in girls Clinical findings Hirsutisms, acne, virilisation of external genitalia, amonorhoe or menstrual cycle disturbance Elevation of androgens - Adrenal (congenital adrenal hyperplasia, tumors) - Ovarian (polycystic ovary syndrome, tumors) - Exogenous (anabolic steroids – doping?) Bone age is accelerated Elevation of testosteron or adrenal androgens

16. Heterosexual pubertal development in boys Clinical findings Gynecomastia, hypogenitalism, eunuchoid body proportions Elevation of estrogens Adrenal or testiscular tumors Administration of Exogenous estrogens Drugs – amfetamin, canabis, tricyclic antidepresives Primary hypogonadism or syndromes with androgen insensitivity or testosteron synthesis disorders (related to ambigous genitalia)

17. Incomplete PP: • Partial development of appropiate secondary sex characteristics, • Premature thelarche seen in girls between 6 months and 2 years of age, • Does not progress to complete puberty (ovulation and mensturation), • Premature adrenarche (growth of axillary and pubic hair) tends to occur between 5 and 8 years of age • Can progress to complete PP; may be caused by estrogen-secreting neoplasms or may be a variant of normal pubertal development…

18. Variants of normal development Premature thelarche (isolated breast enlargement) • exclude the start of precocious puberty! Premature adrenarche (pubic and axillary hairs) • exclude simple virilising form of CAH! Premature menarche • exclude vaginal bleeding due to trauma of vagine or rare ovarian cyst! Bone age is not accelerated! FSH and LH levels after LH-RH are normal Gonadal and adrenal steroid levels are normal Pelvic and adrenal ultrasonography is normal

19. Delayed puberty - definition Initial physical changes of puberty are not present • by age 13 years in girls (or primary amenorhoe at 15.5-16y) • by age 14 years in boys Pubertal development is inappropriate, the interval between first signs of puberty and menarche in girls/completition genital growth in boys is > 5 years

21. In 95% of cases, delayed puberty is a constitutional delay; that is, hormonal levels are normal and the hypothalamic-pituitary-ovarian axis is intact but maturation is happening slowly…

22. GnRH or gonadotropin dependent Idiopathic sporadic or familial (associated with constitutional growth delay) Chronic diseases with bone age delay and growth retardation due to different pathophysical mechanismes (malnutrition, anemia, acidosis, hypoxia,...anorexia nervosa, cystic fibrosis, chronic renal insuficiency,..) Psychosocial deprivation

23. DISORDERS OF MALE REPRODUCTİVE SYSTEM

24. Male Infertility • Infertility can be solely male, solely female, or both • Considered infertile after one year of unprotected intercourse fails to produce a pregnancy • Male problems include • Changes is sperm or semen • Hormonal abnormalities • Pituitary disorders or testicular problems • Physical obstruction of sperm passageways • Congenital or scar tissue from injury • Semen analysis is performed. • The man is evaluated for number, amount, structure, and motility of sperm and obstruction along the reproductive tract.

25. Prostatitis • Pathophysiology • Inflammation of the prostate gland cause by infectious agents • E. coliis the most common • Microorganisms are usually carried to the prostate from the urethra

26. Prostatitis Clinical manifestations • Perinea discomfort • Burning, urgency, frequency & pain after ejaculations • Prostate pain • Dysuria • May produce • Fever and chills • Rectal or low back pain

27. Prostatitis Assessment and diagnostic findings • History • Culture • Histological examination of the tissue • Rectal exam is painfull. • Swollen, tender & firm

28. Benign Prostatic Hypertrophy (BPH)—Pathophysiology • Common in older men; varies from mild to severe • Change is actually hyperplasia of prostate • Nodules form around urethra • Result of imbalance between estrogen and testosterone • No connection with prostate cancer • Rectal exams reveals enlarged gland • Incomplete emptying of bladder leads to infections • Continued obstruction leads to distended bladder, dilated ureters, renal damage • If significant, surgery required

31. BPH—Signs and Symptoms • Initial signs • Obstruction of urine flow • Hesitancy, dribbling, decreased force of urine stream • Incomplete bladder emptying • Frequency, nocturia, recurrent UTIs

32. Prostate Cancer • Common in men older than 50; ranks high as cause of cancer death • 3rd leading cause of death from cancer

33. Prostate Cancer—Etiology • Cause not determined • Genetic, environmental, hormonal factors • Common in North American and northern Europe • Incidence higher in black population than white • Genetic factor? • Testosterone receptors found on cancer cells

34. Dietary Factors • A high intake of fat is a risk factor for prostate cancer. • Fat intake from dairy products increases calcium, itself a proposed risk factor. Ca can suppress circulating levels of dihydroxyvitamin D, a possible protective factor for prostate cancer. • A low intake of dietary fiber and complex carbohydrates and a high intake of protein associated with an increased risk of prostate cancer. • High-enegry intake indicates that this may indeed increase insulin levels and IGF-1. • IGF-1 is known to be a powerful carcinogenic agent.

36. Hormones • Prostate cancer develops in an androgen-dependent epithelum and is usually androgen sensitive. • Androgens promote prostatic epithelial growth during fetal and prepubertal periods. • In adults androgens act through reciprocal homeostatic stromal epithelial interactions to maintain normal differantiation and halt growth. • Their associations are weak: • 1- slightly higher circulating testesterone and estrogen levels and lower DHEA sulfate levels in high-risk African-American men as compared with lower-risk European-American men; • 2- a cytosine-adenine-guanine (CAG) repeat-lenght polymorphism in the androgen-receptor gene associated with increased risk and increased receptor activity.

37. Vasectomy • Three mechanisms by which vasectomy could increase risk are: • 1- elevation of circulating androgens, • 2- immunologic mechanims involving antisperm antibodies, • 3- reduction of seminal fluid levels of 5α-dihydrotestesterone, the active metabolite of testesterone in the prostate, in vasectomized men.

38. Familial Factors • Recent genetic studies suggest that strong familial predisposition may be responsible for 5% to 10% of prostate cancers. • Hereditary cancer is an autosomal dominant disease caused by a rare but highly penetrant gene; that is, 88% of gene carriers develop prostate cancer by age 85 years. • Hereditary cancer differs from the familial form, which occurs in individuals with a positive family history but who do not exhibit early age of onset. • The hereditary form constitutes about 9% of all prostate cancers and approximately 43% of cancers in men less than 55 years of age.

39. Pathogenesis of Prostate Cancer • Testosterone and dihydrotestosterone (DHT) are the most important androgens in the adult male. • Testosterone is the major circulating androgens, whereas DHT predominates in the prostate tissue and binds to the androgen receptor (AR) with greater affinity than does testosterone. • Testosterone is the major androgen from the interstitial cells of the testis (Leydig cells). • In the target tissues, and, to a lesser extend, in the testes themselves, testosterone is converted to DHT by the enzyme 5α-reductase.

40. Thus DHT is the most potent intraprostatic androgen. • Normally, a small amount of estrogen is produced by the aromatization of androgens. • A very small quantity of estradiol is released by the testes; the rest of the estrogens in males are produced by adipose tissue, liver, skin, brain, and other nonendocrine tissues. • Thus testosterone is a precursor of the two hormones, DHT and estradiol.

41. Most of the androgen-metabolizing enzymes undergo a significant age-dependent alteration. • In epithelium, both the 5α-reductase activity and the DHT level decrease with age; whereas in stroma not only is 5α-reductase activity rather constant over the whole age range but also the DHT level is constant as well. • In contrast to the relatively unaltered DHT level, the estrogen content follows an age-dependent increase. • Thus the age-dependent decrease of DHT accumulation in epithelium and the concomitant increase of the estrogen accumulation in stroma lead to a tremendous increase with age of the estrogen/androgen ratio in human prostate.

42. In animal studies, chronic exposure to testosterone plus estradiol is strogly carcinogenic, whereas testosterone alone is weakly carcinogenic. • In addition there are changes in the balance between autocrine/paracrine growth-stimulatory and growth-inhibitory factors, such as IGFs, epidermal GF, nerve GF, IGF-binding proteins and TGF-β.

43. The following multifactorial general hypothesis of prostate carcinogenesis emerges: • 1- androgens act as tumor promoters through androgen receptor-mediated mechanisms to • 2- enhance the carcinogenic activity of strong endogenous DNA toxic carcinogens, including ROS and estrogen-and prostatic generated ROS • 3- alterations in autocrine/paracrine growth-stimulating and growth-inhibiting factors and • 4- possibly unknown environmental-lifestyle carcinogens. • All of these factors are modulated by diet and genetic determinants, such as hereditary susceptibility genes and polymorphic genes (especially steroid 5α-reductase type II).

44. The most common sites of distant metastatis are the lymph nodes, bones, lungs, liver and adrenals.

45. Prostate Cancer—Signs and Symptoms • Hard nodule in periphery of gland • Detected by rectal exam • No early urethral obstruction • As tumor develops, some obstruction occurs • Hesitancy, decreased stream, urinary frequency, bladder infection

46. Gleason Score

47. Prostate Cancer—Diagnostic Tests • 2 helpful serum markers • Prostate-specfic Antigen (PSA) • Useful screening tool for early detection • Prostatic acid phosphatase • elevated when metastatic cancer present • Ultrasound and biopsy confirms

48. DISORDERS OF FEMALE REPRODUCTİVE SYSTEM

49. Disorders of Menstruation • 1- Premenstrual Syndrome (PMS)/Premenstrual Dysphoric Disorder (PMDD): • PMS; is the cyclic recurrence (in luteal phase of the menstrual cycle) of physical, psychologic, or behavioral changes distressing enough to impair interpersonal relationships or interfere with usual activities. • Physical and emotional symptoms occurring 7-10 days prior to menstruation. • Causes: Genetic predisposition, excess estrogen, hypothalamic-pituitary dysregulation; hormonal influence on brain chemicals. • Symptoms:Weight gain, headache, pain, irritability, depression, angry outbursts, social withdraval, fatigue, breast tenderness, abdominal bloating headache, swollen extremities. • Treatment: Healthful lifestyle changes; hormonal therapy; diuretics; vitamin B & Magnesium

50. 2- Dysmenorrhea • Dysmenorrhea is painfull mensturation. • It has two types: Primary and secondary. • Secondary dismenorrhea caused by disorders such as endometriosis, pelvic adhesion, inflammatory disease and uterine fibrosis. • Primary dysmenorrhea is the result of excessive endometrial prostaglandin (PGF2α) production and effect. • These lipid hormones increase myometrial contractions and constrict endometrial blood vessels, causing ischemia, endometrial bleeding and pain. • The latter symptoms are caused by entry of prostaglandins and prostaglandins metabolites into the systemic circulation.