1. Principles of Gynecological Endocrinology

2. Menarche - 1st menstruation
Menopause – last menstruation
Amenorrhea - absence of menstruation
Oligomenorrhea – rare menses (40 d – 6 months)
Hypomenorrhea – reduction in duration and/or amount of menstrual bleeding
Polimenorrhea – frequent menses (less than 25 d)
Hypermenorrhea - long and/or extensive menstrual bleeding
Dysfunctional uterine bleeding – irregularity without organic pathology

3. Reproductive cycle GnRH FSH LH E2 P 1 5 14 21 28 ovulation
No implantation

4. Amenorrhea Primary – woman has menstruated never before
Secondary – 6 months interval after last menstruation

5. Amenorrhea - Causes Pregnancy Hypothalamic-Pituitary Dysfunction
Ovarian dysfunction
Pathology of the genital outflow tract

6. Hypothalamic-Pituitary Dysfunction
Disturbances of the pulsatile manner of the GnRH release or FSH and LH release
Causes
Congenital – Isolated hypogonadotropic hypogonadism
Functional
Weight loss
Excessive exercise
Obesity
Drugs
Psychogenic causes
Anorexia nervosa
Chronic anxiety
Head injury
Neoplastic diseases of the hypothalamo–pituitary region
Diagnosis – medical history; low E2, PRL, low FSH and LH levels; CT; NMR; GnRH test

8. Premature Ovarian failure
Lack of ovarian follicles
Resistance to pituitary stimulation (FSH, LH)
Additional symptoms similar to those associated with menopause
Hot flushes, mood changes, sleep disturbances, headaches, vaginal dryness and/or pruritus, dyspareunia, diaphoresis, altered libido

9. Ovarian failure Causes
Chromosomal abnormalities
45,X gonadal dysgenesis (Turner,s syndrome)
46,XY (Sweyer,s syndrome)
Androgen insensitivity syndrome
Gonadropin-resistant ovary syndrome (Savage’s syndrome)
Premature menopause
Autoimmune ovarian failure (Blizzard’s syndrome)
Iatrogenic – chemo- and radiotherapy, surgery
Diagnosis - medical history; low E2, elevated FSH and LH levels; E-P test, exogenous Gn

10. Pathology of the genital outflow tract
Congenital defects of the uterus and/or vagina preventing menstrual bleeding
Müllerian anomalies
Lack of the uterus and/or vagina (Mayer-Rokitansky-Kuster-Hauser syndrome)
Imperforate hymen
Treatment - surgery
Asherman’s syndrome – scarring of the uterine cavity
After dilation and curettage (D&C)
Treatment – hysteroscopy; E2

11. Obstruction of the genital outflow tract – Congenital defects

12. Amenorrhea - diagnosis
Prolactin serum level
Hyperprolactinemia
Elevated
Normal P
Positive
Anovulation
Negative
E+P
Obstruction of Genital outflow
Negative
Positive
FSH level
Elevated
Decreased
Hypothalamic-Pituitary Dysfunction
Ovarian failure

13. Treatment of the amenorrhea
Congenital – Isolated hypogonadotropic hypogonadism – E and P replacement, exogenous GnRH in pulsatile manner
Functional – changing behavior
Drugs -
Psychogenic causes
Anorexia nervosa
Chronic anxiety
Head injury
Neoplastic diseases - surgery
Prolactin secreting adenoma – bromocriptine
Ovarian failure – hormonal replacement
Obstruction of the genital outflow tract - surgery

14. Dysfunctional uterine bleeding
Irregularity without organic pathology
Usually associated with anovulation (periodical ovulation)
Causes
Hyperprolactinemia
PCOD
Hyperandrogenism
Obesity
Early stage of premature ovarian failure
Unknown
Irregular, extensive uterine bleeding

15. Anovulatory cycle E2 P 1 5 14 21 28
ovulation

16. Dysfunctional uterine bleeding
Chronic estrogen stimulation, unopposed with progesterone
Endometrium outgrows its blood supply
Ischemia, necrosis
The endometrium is partially shed
Irregular, unpredictable, bleeding
The the extent of the bleeding depends on the levels of the estradiol
Infrequent and light
Frequent and heavy
Elongated mitogenic stimulation without progesterone action

17. Dysfunctional uterine bleeding
Luteal phase defect
The ovulation exist
Corpus luteum is poorly developed and insufficient
Shortening of the reproductive cycle
Menses occur earlier than expected
If conception and implantation occur the function of the corpus luteum is not adequate to support the gestation

18. Dysfunctional uterine bleeding - diagnosis
Medical history
Irregular uterine bleeding
Lack of premenstrual symptoms characteristic for ovulatory cycles:
Breast tenderness and fullness, abdominal bloating, mood changes, edema, weight gain, menstrual cramps
Exclusion of the organic causes
Uterus – leyomioma, infection, polyps, neoplasmic diseases
Cervix – polyps, erosions, carcinoma
Vagina – carcinoma, injuries, foreign bodies

19. Dysfunctional uterine bleeding – diagnosis (cont.)
Confirmation of anovulation
BBT
Ultrasound examination
Periovulatory pain
Luteal phase progesterone serum levels
Endometrial biopsy
Proliferative endometrium
Endometrial hyperplasia

21. Dysfunctional uterine bleeding - treatment
Termination of the bleeding (treatment of the acute hemorrhage) - hospitalization
Administration of progestational agent for 10 days – secretory changes in the endometrium
High doses of estrogen and progestational agent
D&C
Establishment of regular cycles (prevention of recurrences) OC
progestational agent – 16th-25th day of cycle
Diagnosis and treatment of
Hyperprolactinemia, PCOS, Hyperandrogenism, Obesity

22. Hyperprolactinemia HYPOTHALAMUS OVARIAN STEROIDS OVARY ANDROGENS
ADRENALS

23. Hyperprolactinemia - Causes
Adenoma and microadenoma
Prolactinoma
Others
Thyroid gland insufficiency – TRH increase
Drugs
Tranquilizers
Antipsychotic (chlorpromazine)
GI stimulant (Metoclopramide)
Estrogens
Methyldopa
Chronic stress
Inadequate regression after labor

24. The effects of elevated level of prolactin
Suppressing pulsatile secretion of GnRH
Decrease in Gn levels
Disturbances in cyclic release of LH in response to the positive feedback of estradiol
Decreased ovary sensitivity to Gn – receptors expression
Stimulation of the adrenal androgens release

25. Hyprprolactinemia - symptoms
Galactorrhea
Delayed menarche
Luteal phase defect
Anovulation
Oligomenorrhea
Primary or secondary amenorrhea

26. Hyprprolactinemia – diagnosis and treatment
Prolactin serum levels
Basal
In dynamic test (MCP, TRH)
CT, NMR
Treatment
Bromocriptine
Surgical treatment

27. PCOS – polycystic ovarian syndrome
Definition
Chronic anovulation or infrequent ovulation
Androgen excess
Metabolic abnormalities
Hyperinsulinemia (50%)
Insulin peripheral tissue resistance

28. PCOS Etiology Genetic predisposition Environmental factors
FOH – functional ovarian hyperandrogenism
FAH - functional adrenal hyperandrogenism

29. PCOS  LH Theca interna stimulation (+) adrostendion  estrone
adipose tissue conversion
androstendione  estrone

30. PCOS Clinical Symptoms Oligomenorrhea or amenorrhea Acne
Hirsutism – excess body hair
Appearance of coarse, dark and dense terminal hair
Obesity (30-50%)
Infertility

32. Hyperandrogenism - symptoms
Hirsutism – excess body hair
Appearance of coarse, dark and dense terminal hair
Acne
Virilization – not present in PCOS
Clitoral enlargement
Deepening of the voice
Involution of the breast
Musculine appearance

33. PCOS Diagnosis Elevated LH serum level Increased LH/FSH ratio
Elevated androstendione serum level
Elevated total testosterone serum level
Elevated estrone serum level
Lowered SHBG
Ultrasound – polycystic ovaries, increased volume of ovaries
BMI

34. PCOS Treatment OC Metformin
Androgen receptor antagonist – cyproterone acetate
5-alpha reductase inhibitors - finasterid
FAH – dexametasone (0,25 md/d)
Ovarian stimulation & ovulation induction

35. Premenstrual syndrome - PMS
The cyclic recurrence during the luteal phase of the menstrual cycle of a combination of distressing physical, psychologic, or behavioral changes that interfere with family, social, or work-related activities
Premenstrual Dysphoric disorder – regular, cyclic occurrence of depressed mood, marked anxiety, affective lability, decreased interest in activities during the last week before the onset of menses
Symptoms
Somatic – breast tenderness and swelling, bloating, constipation or diarrhea, headache, weight gain
Emotional – anxiety, irritability, confusion, crying, depression, changes of libido
Behavioral – cravings, increase appetite, poor concentration

36. PMS - Etiology - theories
Psychiatric
cyclic manifestations of psychopathology
Endocrinologic
abnormality in letal phase sex steroid levels – elevated E2, decreased progesterone
cyclic occurrence of the symptoms
presence of ER and PR in CNS
Endorphin
decrease of endorphin levels in the luteal-phase
PMS symptoms similar to symptoms of opiate withdrawal
Alleviation of symptoms after excessive exercise

37. Cyclic, luteal-phase related, occurrence of the symptoms
PMS - Diagnosis
No specific historical or physical assessment findings or laboratory markers are diagnostic of PMS
Cyclic, luteal-phase related, occurrence of the symptoms
Menstrual diary – monitoring and recording of key symptoms and their severity on a daily basis
Symptom-free follicular phase
Exclusion of organic or functional pathology

38. PMS - Treatment
Cooperation of gynecologist, psychiatrist, psychologist, endocrinologist
Education of the patient
Diet
Fresh fruit and vegetables
Minimizing refined sugars and fats
Frequent small meals
Minimizing salt
Exercise
Medical treatment
Induction of anovulation – OC, Danazol, GnRH analogues
Progesterone
Nonsteroidal anti-inflamatory agents
Diuretics
Anxiolitic and antidepressant medications

40. Puberty - physical, emotional, and sexual transition from childhood to adulthood
Prerequisites
Normal hypothalamus capable of responding to elevated levels of sex steroids by appropriate pulsatile secretion of GnRH
Normal pituitary that is sensitive to GnRH and contains a pool of releasable gonadotropins
Normal ovaries capable of secreting estrogen and progesterone in response to pituitary gonadotropins (FSH, LH)

41. Puberty
The onset of the pubertal event in each individual is variable and influenced profoundly by genetic and environmental factors
The average onset of puberty is between ages 8 and 13 years
The events initiating the onset – unknown
Increased maturity of the hypothalamic-pituitary axis – pulsatile GnRH secretion
CNS appears to control the onset of puberty – an intrinsic CNS inhibitory mechanism suppressing pulsatile GnRH release
Decrease in the CNS inhibitory action  increase in pulsatile GnRH release and pituitary responsiveness

42. Puberty
Adrenarche – at age 8-10 increased secretion of adrenal androgens (DHEA) – pubic and axillary hair growth – precedes the growth spurt by 2 years
Maturation of the axis – increase in Gn response to GnRH
Prepubertal children – minimal response to GnRH – small LH response
Pubertal children – greater LH response to GnRH – sleep-associated gonadotropin secretion
Development of of cyclic release of LH in response to the positive feedback of estradiol

43. Puberty Event Age Hormone Breast budding 10-11 Estradiol
Sexual hair growth 10,5-11,5 Androgens
Growth spurt GH
Menarche 11,5-13 Estradiol
Adult breast development 12,5-15 Progesterone
Adult sexual hair 13,5-16 Androgens

44. Sources of the androgens in female
Hyperandrogenism
Sources of the androgens in female
Dehydroepiandrosterone (DHEA) – suprarenal glands
Androstendion - suprarenal glands; ovaries
Testosterone - suprarenal glands; ovaries; adipose tissue
Functions of the androgens in female
Precursors of the estrogens
Stimulate and maintain sexual hair growth
Responsible for female libido

45. Hyperandrogenism - causes
Increased synthesis and release
PCOD - ovary and/or adrenal glands
Congenital adrenal hyperplasia (21- and 11-hydroxylase deficiency)
Ovarian tumors – Androblastoma, Gynandroblastoma
Adrenal adenoma
Obesity
Increased expression and/or sensitivity of the androgen receptors in peripherial tissues
Increased 5 reductase activity (TDHT)
Constitutional hirsutism
Iatrogenic – glucocorticoids, OC, Danazol

46. Hyperandrogenism - symptoms
Hirsutism – excess body hair
Appearance of coarse, dark and dense terminal hair
Virilization
Acne
Clitoral enlargement
Deepening of the voice
Involution of the breast
Musculine appearance