FERTILITY diaries / ce / BIOMERIEUX and the blue logo, VIDAS are registered and protected trademarks belonging to bioMérieux sa or one of its subsi Investigation of FEMALE REPRODUCTIVE HORMONE DYSFUNCTIONS / RCS Lyon B 398 160 242 B 398/ RCS 160 Lyon bioMérieux sa 69280 Marcy l’Etoile .L. McCANN Santé Lyon T France Tel. : 33 (0)4 78 87 20 00 Fax : 33 (0)4 78 87 20 90 from diagnosis, -04 / 008GB99043A / This document is not legally binding. bioMérieux reserves the right to modify specifications without noti the seeds of better health 09 Printed in France / Printed in France www.biomerieux.com contents Precocious and delayed puberty Secondary amenorrhea Hirsutism Other pathologies : primary amenorrhea and hyperprolactinemia Menopause The approach used for each of the subjects discussed in this booklet is identical : • brief physiological description • clinical approach • basic biological profile • interpretation of results • secondary examinations, if required • treatment Dynamic tests and a list of the main hormone assays are given at the end of the booklet. 1 early follicular phase late follicular phase luteal phase D-3 ➭ D5 = selective follicular recruitment Endorphins Dopamin Adrenalin Endorphins Dopamin Adrenalin - - - + - + hypothalamus hypothalamus hypothalamus - - - + pulsatile GnRH + pulsatile GnRH + pulsatile GnRH - pituitary pituitary pituitary - LH + LH LH FSH/LH>1 FSH FSH FSH + + - + + ++ + LE IC L L O F Cholesterol Cholesterol Cholesterol Follicular phase Pre-ovulatory phase Androgens Androgens Androgens VULATION 4-Androstenedione 4-Androstenedione, O 4-Androstenedione, Testosterone, ... Testosterone, ... Pg E2 AROMATASE AROMATASE AROMATASE Inhibin B PGE, PGF2, IGF-I, E2 E2 E2 E2 E2 IGF-I Inhibin B small cells large cells ≤ 40 pg/ml theca interna Steroidogenesis : LH-dependent / Aromatization : FSH-dependent ovulatory peak theca externa of LH vascularization estradiol progesterone FSH granulosa cells HORMONE SECRETIONS E2 . Estradiol HORMONAL PHYSIOLOGY Pg . Progesterone GnRH . Gonadotropin Releasing Hormone FSH, LH . Gonadotropins IGF . Insulin-like Growth Factor PGE, PGF . Prostaglandins TEMPERATURE CURVE 37°C follicular phase peri-ovulatory phase luteal phase st D-3 D0 = 1 day of menstruation D14 D28 LH receptor 2 selective follicular recruitment3 follicular maturationovulation Corpus luteum atretic Corpus luteum 4 puberty precocious puberty biochemical mechanisms Onset of puberty before the age of 8 (European population). Central Nervous System (CNS) CLINICAL SIGNS PUBERTY inhibition Breast development and/or growth of pubic and suppressed - axillary hair. NITIAL PROFILE increase in GnRH I hypothalamus pulsatility and This profile aims to differentiate between : It comprizes : - secretion peaks ➢ isolated pubic and axillary hair growth (pubarche) ➢ basic FSH and LH levels + LH-RH test (GnRH) GnRH ➢ isolated breast development (thelarche) ➢ Estradiol ➢ central precocious puberty ➢ DHEAS to evaluate adrenal maturation ➢ primary precocious puberty or adrenarche increase in the number (pseudoprecocious puberty) ➢ evaluation of stature and bone age of GnRH-receptors • • • • • INTERPRETATION OF RESULTS pituitary increase - secondary sexual Isolated or predominant More or less LH FSH in gonadotropin characteristics breast development Predominant or isolated axillary hair growth balanced pulsatility and development secretion peaks basic FSH-LH levels FSH➡ lowLH ➡ normal or low normal or increased • • • • response FSH➡ prepubertal LH➡ prepubertal pubertal • • • • increase in • or low gonadal steroid inhibition suppressed to LH-RH test ovary the number of FSH- and PRECOCIOUS OVARIAN PRIMARY adrenal disorders TRUE PRECOCIOUS LH-receptors THELARCHE PRECOCIOUS PUBERTY PUBERTY (OR CENTRAL) (OR PSEUDOPRECOCIOUS PUBERTY) • abdominal-pelvic • abdominal-pelvic radio-imaging • cerebral increase secondary examinations E for confirmation radio-imaging techniques techniques radio-imaging 2 in E production • associated endocrine disorders • 4-Androstenedione, testosterone, techniques 2 or orientation • skeleton radiography DHEAS, 17-OH Progesterone ovarian functional PRECOCIOUS ADRENAL GLAND CENTRAL tumor cysts PUBARCHE PRIMARY NEUROGENIC (ADRENARCHE) PRECOCIOUS PUBERTY OR IDIOPATHIC decrease in the concentration of (OR PSEUDOPRECOCIOUS PRECOCIOUS Sex Hormone Binding Globulin SHBG McCune-Albright PCO syndrome PUBERTY) PUBERTY dynamic tests synacthene, dexamethasone tumor Cushing’s syndrome Complete pubertal development takes 2 to 3 years. It is preceded hyperplasia by an adrenal maturation phase (at the age of 6 or 7) known (21-hydroxylase deficiency) as the adrenarche, biochemically characterized by an increase TREATMENT in circulating DHEAS*. •In cases of true central precocious puberty, pubertal •Treatment of congenital adrenal hyperplasia (CAH). *Dehydroepiandrosterone sulfate. development is halted using an LH-RH agonist •Treatment of the tumor, if required. (an annual LH-RH test controls the degree of pituitary blockage). 5 6 7 delayed puberty No signs of puberty after the age of 13 - 14 (European population). CLINICAL SIGNS PUBERTY No breast development, nor pubic and axillary hair growth. INITIAL PROFILE This profile aims to differentiate between : It comprizes : ➢ delayed puberty ➢ basic FSH and LH levels + LH-RH test (GnRH) ➢ hypogonadotropic hypogonadism ➢ Estradiol ➢ hypergonadotropic hypogonadism ➢ DHEAS to evaluate adrenal maturation or adrenarche ➢ evaluation of stature and bone age for orientation of diagnosis to delayed puberty ➢ assay of prolactin to eliminate hyperprolactinemia INTERPRETATION OF RESULTS secondary sexual No breast development characteristics No pubic and axillary hair growth basic FSH-LH levels normal or low low high response prepubertal low even nil pubertal or increased to LH-RH test response differential diagnosis : family history, delayed stature growth and bone maturation, DHEAS low DELAYED PUBERTY HYPOGONADOTROPIC HYPERGONADOTROPIC 1 IN EVERY 5 CASES HYPOGONADISM HYPOGONADISM secondary examinations • cerebral radio-imaging techniques • abdominal-pelvic • GH, TSH, Cortisol, 4-Androstenedione radio-imaging techniques for confirmation • karyotype or orientation • investigation of a specific genetic disorder Panhypopituitarism Isolated gonadotropic Pure ovarian Turner's (congenital or acquired) insufficiency dysgenesis syndrome syndrome miscellaneous causes : • visceral or general Specific genetic disorder (e.g. : chronic renal failure) (e.g. Testicular Feminization • endocrinopathy Syndrome) (e.g. : hypothyroid, hypercortisolism) • psychological or social (e.g. : anorexia) TREATMENT substitutive (estrogen then estrogen-progestrone), except in cases of delayed puberty. 8 9 secondary amenorrhea (without hirsutism) Women < 46 yrs old CLINICAL SIGNS - no specific clinical signs - no menses for over 3 months Anamnesis : Background history of : Date of last childbirth, variation in weight, drugs, - chemotherapy and radiotherapy. genital and breast examination, stop estrogen- - surgery (ectopic pregnancy, ovariectomy, progesterone treatment, affective shock... appendicectomy...). - infection (salpingitis, STD, tuberculosis) INITIAL PROFILE Firstly : Then : ➢ assay hCG to exclude pregnancy ➢ FSH, Estradiol, (LH) AMENORRHEA if hCG negative, make an appointment in 1 to 2 weeks ➢ Prolactin (PRL) time using a menothermal curve (to exclude pregnancy ➢ TSH if apathy and/or weight gain. or trophoblastic tumor) Hypothyroidism (increased TSH) leads to an increase in TRH which stimulates PRL secretion. INTERPRETATION OF RESULTS hCG : negative TSH : normal or regulated Basic tests PRL FSH increased normal E2 normal increased ≥40 pg/ml or low initial profile if after halting treatment : Progesterone test - early ovarian insufficiency ? PRLvvvvvvv➡ ➡ - anti-ovarian Ab ? secondary • iatrogenous origin Positive Negative Estradiol to evaluate examinations (bleeding) (no bleeding) • adenoma (radio-imaging ovocytic maturation for confirmation techniques of the sella turcica (early menopause : “normal” or and orientation and visual field) Etiologies highly fluctuating levels of E2) - Infection - Endometrium lesion (following curettage) Additional investigations and/or - Physical / Psychological trauma action to be taken : (central amenorrhea) - Sport at competitive level Either desire for pregnancy : - Adenoma / adrenal tumor or secreting ovary ? - FSH, LH, E E2, Cortisol, Testo 2 - Recent non-secreting pituitary adenoma - Ovulation induction - Hemorrhagic childbirth (Sheehan's syndrome) Or wait : Depending on etiology - For menses to return - Hysteroscopy - Laparoscopy - FSH and LH control - Endometrium, cervix biopsy - Cyclic progesterone treatment, - Pelvic radio-imaging techniques if required - Scan, NMR 10 11 Secondary amenorrhea / spaniomenorrhea with hirsutism CLINICAL SIGNS No menses for over 3 months or 2 to 4 cycles per year. •hirsutism : excess hair growth in regions stimulated Anamnesis : by sexual hormones. - date of puberty - regularity of menses Possible to grade (0 to 4) the level of excess hair. - weight gain Hirsutism is pathological while hypertrichosis is - evolution of hirsutism - treatment in progress ethnic and family-related - menothermic curves • acne, seborrhea • possible obesity (android fat distribution ?) • recent signs of virilization (voice deepening, clitoromegaly...) INITIAL PROFILE (before D5 if spaniomenorrhea) This profile aims to distinguish : It comprizes : ➢ the origin of hyperandrogenia ➢ FSH, LH, Prolactin (PRL), ∆ (ovarian, adrenal or idiopathic). ➢ Testosterone (T), E2,