Principles of Gynecological Endocrinology

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

Reproductive cycle

1 5 14 28

FSH

E2

21P

LH

GnRH

ovulation

No implantation

Amenorrhea

Primary – woman has menstruated never before

Secondary – 6 months interval after last menstruation

Amenorrhea - Causes

Pregnancy

Hypothalamic-Pituitary Dysfunction

Ovarian dysfunction

Pathology of the genital outflow tract

Hypothalamic-Pituitary Dysfunction

Disturbances of the pulsatile manner of the GnRH release or FSH and LH releaseCauses 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

Premature Ovarian failure

Lack of ovarian folliclesResistance to pituitary stimulation (FSH, LH)Additional symptoms similar to those associated with menopauseHot flushes, mood changes, sleep

disturbances, headaches, vaginal dryness and/or pruritus, dyspareunia, diaphoresis, altered libido

Ovarian failureCauses 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

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

Obstruction of the genital outflow tract – Congenital defects

Amenorrhea - diagnosis Prolactin serum level

Elevated Normal

Negative Positive

Positive Negative

Elevated Decreased

HyperprolactinemiaP

E+P

Obstruction of Genital outflow

FSH level

Anovulation

Ovarian failure

Hypothalamic-Pituitary Dysfunction

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

Dysfunctional uterine bleeding

Irregularity without organic pathologyUsually associated with anovulation (periodical ovulation)Causes Hyperprolactinemia PCOD Hyperandrogenism Obesity Early stage of premature ovarian failure Unknown

Irregular, extensive uterine bleeding

Anovulatory cycle

1 5 14 28

E2

21P

ovulation

Dysfunctional uterine bleeding

Chronic estrogen stimulation, unopposed with progesterone

Endometrium outgrows its blood supplyIschemia, necrosisThe endometrium is partially shedIrregular, 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

Dysfunctional uterine bleeding

Luteal phase defectThe ovulation existCorpus luteum is poorly developed and

insufficientShortening of the reproductive cycleMenses occur earlier than expected If conception and implantation occur the

function of the corpus luteum is not adequate to support the gestation

Dysfunctional uterine bleeding - diagnosis

Medical history Irregular uterine bleedingLack of premenstrual symptoms

characteristic for ovulatory cycles: Breast tenderness and fullness, abdominal

bloating, mood changes, edema, weight gain, menstrual cramps

Exclusion of the organic causesUterus – leyomioma, infection, polyps,

neoplasmic diseases Cervix – polyps, erosions, carcinomaVagina – carcinoma, injuries, foreign

bodies

Dysfunctional uterine bleeding – diagnosis (cont.)

Confirmation of anovulationBBTUltrasound examinationPeriovulatory painLuteal phase progesterone serum levels

Endometrial biopsy Proliferative endometriumEndometrial hyperplasia

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

HyperprolactinemiaHYPOTHALAMUS

ADRENALS

OVARYOVARIAN STEROIDS

ANDROGENS

Hyperprolactinemia - Causes

Adenoma and microadenoma Prolactinoma Others

Thyroid gland insufficiency – TRH increase Drugs Tranquilizers Antipsychotic (chlorpromazine) GI stimulant (Metoclopramide) Estrogens Methyldopa

Chronic stressInadequate regression after labor

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

Hyprprolactinemia - symptoms

Galactorrhea

Delayed menarche

Luteal phase defect

Anovulation

Oligomenorrhea

Primary or secondary amenorrhea

Hyprprolactinemia – diagnosis and treatment

Diagnosis

Prolactin serum levels Basal In dynamic test (MCP, TRH)

CT, NMR

Treatment

Bromocriptine

Surgical treatment

PCOS – polycystic ovarian syndrome

Definition

Chronic anovulation or infrequent ovulation

Androgen excess

Metabolic abnormalitiesHyperinsulinemia (50%) Insulin peripheral tissue resistance

Etiology

Genetic predisposition

Environmental factors

FOH – functional ovarian hyperandrogenism

FAH - functional adrenal hyperandrogenism

PCOS

PCOS

LH

Theca interna stimulation (+)

adrostendion estrone

adipose tissue conversionandrostendione estrone

Clinical SymptomsOligomenorrhea or amenorrheaAcne Hirsutism – excess body hairAppearance of coarse, dark and dense

terminal hair

Obesity (30-50%)Infertility

PCOS

Hyperandrogenism - symptoms

Hirsutism – excess body hairAppearance of coarse, dark and dense

terminal hair

Acne

Virilization – not present in PCOSClitoral enlargementDeepening of the voice Involution of the breastMusculine appearance

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

PCOS

PCOS

Treatment

OC

Metformin

Androgen receptor antagonist – cyproterone acetate

5-alpha reductase inhibitors - finasterid

FAH – dexametasone (0,25 md/d)

Ovarian stimulation & ovulation induction

Premenstrual syndrome - PMSThe 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

SymptomsSomatic – breast tenderness and swelling, bloating, constipation or diarrhea, headache, weight gainEmotional – anxiety, irritability, confusion, crying, depression, changes of libidoBehavioral – cravings, increase appetite, poor concentration

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

PMS - DiagnosisNo specific historical or physical assessment findings or laboratory markers are diagnostic of PMSCyclic, luteal-phase related, occurrence of the symptomsMenstrual diary – monitoring and recording

of key symptoms and their severity on a daily basis

Symptom-free follicular phaseExclusion of organic or functional pathology

PMS - Treatment

Cooperation of gynecologist, psychiatrist, psychologist, endocrinologistEducation of the patient Diet Fresh fruit and vegetables Minimizing refined sugars and fats Frequent small meals Minimizing salt

ExerciseMedical treatment Induction of anovulation – OC, Danazol, GnRH analogues Progesterone Nonsteroidal anti-inflamatory agents Diuretics Anxiolitic and antidepressant medications

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)

PubertyThe 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 yearsThe events initiating the onset – unknownIncreased maturity of the hypothalamic-pituitary axis – pulsatile GnRH secretionCNS 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

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

Puberty

Event Age Hormone

Breast budding 10-11 Estradiol

Sexual hair growth 10,5-11,5 Androgens

Growth spurt 11-12 GH

Menarche 11,5-13 Estradiol

Adult breast development 12,5-15Progesterone

Adult sexual hair 13,5-16 Androgens

Hyperandrogenism

Sources of the androgens in female Dehydroepiandrosterone (DHEA) – suprarenal

glandsAndrostendion - suprarenal glands; ovariesTestosterone - suprarenal glands; ovaries;

adipose tissue

Functions of the androgens in femalePrecursors of the estrogensStimulate and maintain sexual hair growthResponsible for female libido

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 (TDHT) Constitutional hirsutism

Iatrogenic – glucocorticoids, OC, Danazol

Hyperandrogenism - symptoms

Hirsutism – excess body hairAppearance of coarse, dark and dense

terminal hair

VirilizationAcneClitoral enlargementDeepening of the voice Involution of the breastMusculine appearance