Disorders of Female Reproduction 2024 PDF

Disorders of Female Reproduction Marizna Korf Division of Chemical Pathology 2024 [email protected] Learning Outcomes Describe the role of the hypothalamic-pituitary-gonadal system in controlling the female reproductive system Desc...

Disorders of Female Reproduction Marizna Korf Division of Chemical Pathology 2024 [email protected] Learning Outcomes Describe the role of the hypothalamic-pituitary-gonadal system in controlling the female reproductive system Describe the effects of gonadotrophic hormones on the ovaries Define puberty, menarche and menopause in the context of the hormonal changes in the ovarian cycle List the biochemical and physical changes that occur in puberty Describe the structure, secretion, synthesis and function of oestrogen and progesterone in the context of the female reproductive system Discuss an approach to investigating amenorrhoea, PCOS and hirsutism. Handbook Hypothalamic-pituitary-gonadal (HPG) axis FSH: follicle-stimulating hormone Stimulates growth of follicles LH: luteinising hormone Turns the follicle into the corpus luteum (luteinisation) by triggering ovulation © 2021 UpToDate, Inc. and/or its a8iliates. All Rights Reserved.  Menopause: Permanent cessation of menstruation from physiological loss of ovarian function Puberty: Follicle numbers decrease steadily with age At menopause few or none left Increased GnRH pulsatility Younger females: “primary ovarian insu4iciency” Increased ovarian oestradiol secretion Hormones 12 consecutive months of amenorrhoea Mean age 51 years Oestradiol: linear growth and breast Peri-menopause: development (thelarche – earliest sign of FSH rises 1-2 years before menopause sexual development) LH unchanged initially Adrenarche: onset of adrenal Oestrogen normal until few months before Post-menopause: androgen secretion (8-12 years) Androgens: axillary and pubic hair 27 28 1 2 FSH and LH significantly elevated (FSH higher) 26 3 Menarche: initiation of menses, 4 >90% decrease in oestrogen 25 Increased risk of coronary heart disease and 2-3 years after onset of puberty 24 5 osteoporosis 23 6 22 7 Hypothalamic-pituitary axis is 21 8 highly sensitive to negative 20 9 feedback by gonadal steroids 19 10 Low gonadal steroids and low gonadotropins 18 11 17 12 16 15 14 13 Hormones Ovarian Steroid Hormones Oestradiol Oestrogen: Principle ovarian hormone is oestradiol Small amounts of oestrone, mostly from androstenedione conversion in Oestrone ovaries Other tissue sources: Corpus luteum, placenta Functions: Female 2o sexual characteristics: bone growth, uterine thickening, breast development Oestrogen also a,ects the skin, vascular smooth muscle and central nervous system. Concentrations throughout lifespan: low before puberty → cyclical changes → low concentrations during menopause (source: metabolism of adrenal androgens) Cyclical changes in oestrogen concentration: Negative feedback switch to positive feedback prior to ovulation (mechanism unknown) The rapid rise in oestrogen before ovulation stimulates LH release (Positive feedback) ECect on plasma proteins: Stimulates synthesis of sex hormone-binding globulin (SHBG) and other proteins (eg thyroxine binding globulin) Image: N.Pandey, slideshare.net Concentrations in plasma: only 2-3% is free and biologically active (60% bound to albumin, rest to SHBG) Hormones Ovarian Steroid Hormones Progesterone: Sources: Intermediate in the steroid biosynthesis pathway; by corpus luteum and placenta Cyclical change: Rises in second half of menstrual cycle, then falls if no conception Functions/e+ects: Uterus: Promotes secretions and prepares endometrium for implantation of fertilised ovum; maintains early pregnancy Pyrogenic: Increase in body temp occurs with ovulation Other: thickening of cervical mucus, reduce uterine contractions In plasma: 1-2% free, extensively bound to albumin and transcortin Day 21 measurement useful in investigation of infertility Hormones Ovarian Steroid Hormones Androgens: Ovaries produce: androstenedione, dehydroandrostenedione, testosterone and dihydrotestosterone Less free testosterone Testosterone is present at a ten-fold lower concentration than in males (biologically active fraction) Highly bound to proteins (Sex Hormone Binding Globulin_SHBG) SHBG is twice the SHBG level of males (increased oestrogen eFects) SHBG binds both testosterone and oestradiol (Greater aFinity for testosterone) Please refer to Changes in SHBG concentration aFect the free concentration of sex steroids SHBG in Male Reproduction Low SHBG = increase free testo:oestrogen ratio = increased androgen ePects lecture for Excess androgens= hirsutism, loss of female characteristics, conditions that masculinisation/virilisation increase or decrease SHBG Ovarian androgen synthesis continues after menopause Note: Androgens also produced by adrenals, DHEA is mostly derived from the peripheral conversion of adrenal androgens. Role of Adrenal Androgens in females: muscle growth, pubic and axillary hair at puberty  Follicular Phase Midcycle Luteal Phase Overview of the menstrual cycle Day 1: menses begins Two phases of parallel events: Ovaries: Follicular and Luteal Endometrium: Proliferative and secretory Follicular phase: 10-16 days (variable) Luteal phase: 14 days (Constant) Peak LH occurs 10-12hrs before ovulation (day 14) Ruptured follicle becomes corpus luteum (produces progesterone and some E2) Day 21: Progesterone max. (use as a test of ovulation) Oestrogen is responsible Increased oestrogen Progesterone is the dominant for the changes to the secretion by dominant follicle hormone in the luteal phase endometrium during the results in the LH surge follicular phase Deficiency = irregular and incomplete Deficiency = failure of development of the endometrium implantation of embryo  Disorders of Increased the HPG axis androgens Disorders of female gonadal function PCOS nes 1° Never menstruated mo Hor 2° Changes in Amenorrhoea or Precocious puberty Oligomenorrhoea menstruation or delayed puberty Enter puberty either 27 28 1 2 26 3 too early or too late 25 4 Menopause Primary ovarian 24 5 too early insu,iciency 23 6 22 7 21 8 20 9 19 10 18 11 17 12 16 15 14 13 Amenorrhoea Absence of menstruation for > 3 months Primary vs Secondary Primary: Absence of menses at 15 years of age, in the presence of normal growth and secondary sexual characteristics (Failure to reach menarche) – Never menstruated Secondary: Cessation of regular menses for 3 months or irregular menses for 6 months – had at least one menstrual cycle Work-up dependent on history and examination Oligomenorrhoea: infrequent or irregular menstrual bleeding, long menstrual cycles (35-40 days)  Compare to the causes of male hypogonadism Amenorrhoea: Causes Hypothalamic disorders Kallmann’s syndrome Hypothalamus Hypothalamic infiltration Craniopharyngioma 2° GnRH Weight loss, stress, exercise (hypothalamic) E2 ⬇; FSH and LH ⬇ Pituitary disorders Pituitary Prolactin secreting tumour Granulomatous infiltration (e.g. TB, sarcoid) FSH LH Sheehan’s syndrome Ovarian disorders 1° Ovary Gonadal dysgenesis (Turner’s syndrome: 45XO) E2 ⬇; FSH and LH ⬆ Premature ovarian failure (idiopathic, autoimmune, viral, chemo, radiation) Oestrogen Progesterone Outflow tract/uterus disorders Mullerian duct anomalies Uterus Androgen insensitivity syndrome Asherman’s syndrome (endometrial destruction) Other endocrine disorder Klein M, Poth M. Am Fam Phys. 2013. Approach to 1º Amenorrhoea Klein M, Poth M. Am Fam Phys. 2013. Approach to 2º Amenorrhoea Polycystic Ovarian Syndrome (PCOS) Features: Menstrual irregularities and infertility Hyperandrogenism (Clinical: hirsutism, acne, male pattern balding or biochemically - elevated androgens) Central obesity (50%) Insulin resistance Polycystic ovaries: Multiple ovarian follicles – failure to develop a dominant follicle = constant oestrogenic stimulation of the endometrium Image: drmangelo.com PCOS Complex disorder: disruption of pituitary-ovarian axis Overproduction of ovarian androgens: testosterone, androstenedione, DHEA-S Androgens and insulin suppress hepatic SHBG synthesis therefore more free testosterone = androgen e\ect GSH measure total testosterone and SHBG, therefore use free androgen index = total testo/SHBG Biochemical pattern: Oestradiol normal, high LH and normal FSH Image: Franks, S. NEJM. 1995 Hirsutism Male pattern of hair growth A feature of hyperandrogenism and often associated with menstrual irregularity Causes: ovarian (PCOS, tumour) adrenal (congenital adrenal hyperplasia, tumour) Cushing’s syndrome idiopathic drugs (anabolic steroids, phenytoin, danazol) Image: independentnurse.co.uk Hirsutism History and physical exam will guide laboratory testing: - serum testosterone - SHBG (testo and SHBG to assess FAI) - DHEA-S (adrenal androgen production – only measure in severe hyperandrogenism, symptoms suggestive of androgen-secreting tumour; require imaging if DHEA-S>18.9umol/L) - 17-OH progesterone (to exclude late onset CAH with 21 hydroxylase def) - Cortisol (to exclude Cushings) Concerning features: What is meant by - virilisation virilisation? - Serum testosterone > 5.2 nmol/L - rapid onset - palpable abdominal mass Image: Udhreja et al. IJPM. 2014 Thank you  Optional Changes in SHBG SHBG present in nanomolar concentrations, very little. Testosterone inhibit Oestrogen 60% bound to Stimulate formation albumin, but less albumin present in liver cirrhosis, synthesis therefore more free oestrogen. A lot of the clinical features of chronic liver disease (spider nevi, Increased Glucocorticoids – increase in insulin gynaecomastia and palmar oestrogen resistance. Insulin directly decreases SHBG erythema) are due to dysregulation of steroid Inverse The mechanism by which obesity is hormones, especially correlation with associated with lowered SHBG has not oestrogen. weight been fully elucidated but may involve suppression of hepatic SHBG synthesis by SHBG significantly higher in patients elevated concentrations of insulin. with anorexia, but levels of oestrogen, testosterone and fT3 are lower. Inverse correlation with weight. No clear mechanism.