Male Hypogonadism Jan 23 (wecompress.com).pptx

Endocrine aspects of male hypogonadism Dr Rajesh Govindan Consultant in Diabetes & Endocrinology Princess Royal Hospital Topics • Physiology of testosterone secretion, control and actions • Primary and secondary hypogonadism • Gynaecomastia • Testosterone treatment Learning Outcome(s): to underst...

Endocrine aspects of male hypogonadism Dr Rajesh Govindan Consultant in Diabetes & Endocrinology Princess Royal Hospital Topics • Physiology of testosterone secretion, control and actions • Primary and secondary hypogonadism • Gynaecomastia • Testosterone treatment Learning Outcome(s): to understand the physiology of testosterone secretion in the male, causes of low testosterone, investigations and management of hypogonadism Testes : Normal Anatomy and Histology Gray’s Anatomy for students 2nd ed Gray’s Anatomy for Students Testosterone: Testes The testes contain two anatomical units: • Seminiferous tubules in which inhibin B and anti-Müllerian hormone are synthesized by Sertoli cells and sperm are produced. • An interstitium containing Leydig cells that produce Testosterone. Physiology of Testosterone secretion, control and action Testosterone regulation The hypothalamic-pituitary-testicular axis Guyton and Hall Textbook of Medical Physiology, 12th Ed Testosterone: The hypothalamic-pituitary-testicular axis • Pulsatile secretion of GnRH • Secretion of LH and FSH • LH and FSH are composed of two glycoprotein chains. • LH is involved in release of Testosterone • FSH is involved in spermatogenesis Testosterone synthesis Iain J McEwan, PhD and Albert O. Brinkmann, PhD, Endotext, July, 2021 Testosterone • Steroid hormone • Secreted both in men and women – Testes, Ovary and Adrenal • Normal young men produce about 7 mg each day, of which less than 5% is derived from adrenal secretions • Testosterone in blood is largely bound to plasma protein, with only about 2 % present as free hormone • About half (>50%) is bound to albumin, • 44% is bound to sex hormone-binding globulin (SHBG) Androgens : Synthesis CHOLESTEROL NADPH LH P450 scc Pregnenolone Progesterone Dehydroepiandrosterone (DHEA) Testosterone 5-Reductase Dihydrotestosterone (DHT) Aromatase Estradiol FSH Testosterone: Mechanism of Action • Like other steroid hormones, testosterone penetrates the target cells whose growth and function it stimulates • Androgen target cells generally convert testosterone to 5 α-dihydrotestosterone before it binds to the androgen receptor • Alternatively, testosterone can be aromatized to estrogens, which exert effects that are independent of, opposite to, or synergistic to those of androgen • • • • Testosterone (T) Androgen receptor (AR) 5 α-dihydrotestosterone (DHT) The thickness of the arrows reflects the quantitative importance of each reaction Testosterone action • Regulation of gonadotropin secretion by the hypothalamicpituitary system • Initiation and maintenance of spermatogenesis • Formation of the male phenotype during embryogenesis • Promotion of sexual maturation at puberty and its maintenance thereafter • Increase in lean body mass and decrease in fat mass Male hypogonadism Male Hypogonadism Defined as failure of testes to produce adequate Testosterone • Steroid hormone • Secreted both in men and women – Testes, Ovary and Adrenal • Normal young men produce about 7 mg each day, of which less than 5% is derived from adrenal secretions • Testosterone in blood is largely bound to plasma protein, with only about 2 % present as free hormone • About half (>50%) is bound to albumin, • 44% is bound to sex hormone-binding globulin (SHBG) Normal Testosterone secretion over a life time Griffin JF, Wilson JD: The testis. In: Bondy PK, Rosenberg LE [eds]: Metabolic Control and Disease, 8th ed. Philadelphia: WB Saunders Male Hypogonadism • Defined as failure of testes to produce adequate Testosterone • Decrease in one or both of the two major functions of the testes: sperm production or testosterone production. • Disease of the testes (primary hypogonadism) or disease of the hypothalamus or pituitary (secondary hypogonadism) • Primary hypogonadism: Testosterone below normal and the serum LH and/or FSH are above normal. • Secondary hypogonadism: Testosterone below normal and the serum LH and/or FSH are normal or low. Male Hypogonadism : Causes Primary Secondary • Klinefelter syndrome • Cryptorchidism • Infection-mump • Radiation • Trauma • Torsion • Idiopathic • Congenital GnRH deficiency • Hyperprolactinemia • Androgen intake • Opioids • Illness • Anorexia nervosa • Pituitary disorder Male Hypogonadism :Clinical feature • First trimester – female genitalia to ambiguous genitalia to partial virilization • Third trimester – micropenis • Prepubertal – failure to undergo or complete puberty • Adults Symptoms/ Signs of hypogonadis m • Incomplete sexual development, eunuchoidism • Sexual desire & activity • Spontaneous erections • Gynecomastia • Body hair (axillary & pubic), shaving • Very small or shrinking testes (esp < 5 ml) • Inability to father children, low/zero sperm counts • Height, low-trauma fracture, low BMD • Muscle bulk & strength • Hot flushes, sweats Less Specific Symptoms/Si gns of hypogonadis m • energy, motivation, initiative, aggressiveness, self-confidence • Feeling sad or blue, depressed mood, dysthymia • Poor concentration and memory • Sleep disturbance, increased sleepiness • Mild anemia • Normochromic, normocytic. • Increased body fat, BMI • Diminished physical or work performance Conditions with a High Prevalence of hypogonadi sm (Screening Suggested) • Pituitary mass, radiation to pituitary • On meds that affect T production or metabolism • Glucocorticoids, ketoconazole, opioids • HIV-associated weight loss • ESRD and maintenance hemodialysis • Moderate to severe COPD • Osteoporosis or low trauma fracture (esp if young) • Type 2 diabetes mellitus • Infertility Relevant Medical History • • • • • • • • • Puberty and sexual development Past/present major illnesses Past/present nutritional deficiency All prescription & nonprescription drugs Relationship problems Sexual problems Major life events Related family history Recent changes in body (breasts) Male hypogonadism : Examination • Body hair • Breast exam for enlargement/tenderness • Size and consistency of testicles (orchidometer) • Size of the penis • Signs of severe & prolonged hypogonadism • Loss of body hair • Reduced muscle bulk and strength • Osteoporosis • Smaller testicles • Arm span Male hypogonadism : Investigations • Serum testosterone • LH/FSH • SHBG • LFT • Semen analysis • Karoyotyping • Pituitary function testing • MRI • DEXA scan Male hypogonadism : Guidelines on Screening • Initial screen = morning total testosterone • Levels are highest in the morning • Normal testosterone is generally age dependent • Confirmation = repeat morning total testosteron • Free or bioavailable • Do not screen during acute or subacute illness • Illness, malnutrition, and certain medications may temporarily lower testosterone Brighton and Sussex pathology https://www.frontierpathology.nhs.uk/pug/10-test-lists/453-testosterone? highlight=WyJ0ZXN0b3N0ZXJvbmUiXQ== History and Physical (Symptoms and Signs) Morning Total Testosterone Normal Testosterone Low Testosterone Exclude reversible illness, drugs, nutritional deficiency Not Hypogonadism Follow up Do you suspect altered SHBG? Semen Repeat Testosterone analysis Check LH+FSH if fertility issue If altered SHBG Use free or bio T Normal Testosterone, LH+FSH Testosterone Circulates Mostly Bound to Sex Hormone Binding Globulin What lowers SHBG • • • • Moderate obesity Nephrotic syndrome Hypothyroidism Use of • Glucocorticoids • Progestins • Androgenic steroids What raises SHBG • • • • • • Aging Hepatic cirrhosis Hyperthyroidism Anticonvulsants Estrogens HIV infection Confirmed low or free testosterone Low Testosterone Low or normal LH+FSH Low Testosterone High LH+FSH Secondary Hypogonadism Primary Hypogonadism Prolactin, iron sats Other pituitary hormones MRI in certain cases Karyotype Klinefelter Syndrome Other Testicular Insult Treatment Testosterone • Gel • Injection • Buccal/Patch/Pellet Monitoring • Testosterone • PSA • FBC • DRE • DEXA Contraindications to Testosterone Therapy • Breast or prostate cancer • Lump/hardness on prostate exam by DRE • PSA >3 ng/ml that has not been evaluated for prostate cancer • Severe untreated BPH (AUA/IPSS >19) • Erythrocytosis (hematocrit >50%) • Hyperviscosity • Untreated obstructive sleep apnea • Severe heart failure (class III or IV) Gynecomastia Gynecomastia : Introduction • Gynecomastia, a benign proliferation of the glandular tissue of the male breast • It may be unilateral or bilateral • diagnosed on exam as a palpable mass of tissue at least 0.5 cm in diameter (usually underlying the nipple). • Imbalance between androgen and estrogen • 60% of boys during puberty – transient • 30-70% in adult men Gynecomastia Gynecomastia :Causes • Persistent pubertal gynecomastia • Drugs • Idiopathic • Cirrhosis or malnutrition • Hypogonadism • Testicular tumour • Hyperthyroidism • Chronic renal insufficiency –Leydig cell dysfunction Gynecomastia :Evaluation • Is the breast enlargement of recent onset or associated with pain or tenderness? • Is the breast enlargement due to increased glandular tissue or is it only adipose tissue (pseudogynecomastia)? • Are there findings suggestive of breast cancer? • Is there evidence of a testicular tumor, which might lead to gynecomastia by producing estrogen or stimulating its production? • Can a cause for the breast enlargement be identified? • Is the patient troubled by the breast enlargement? Gynecomastia : History • Duration • Breast pain/tenderness • Systemic disease • Weight gain or loss • Use of medication/recreational drugs • Exposure to chemicals • Fertility • Sexual function • Family hsitory Gynecomastia : Examination • Virilisation • Testicular size • Penis • Sign of CLD or CRF • Thyroid • Breast Gynecomastia: Investigation • Testosterone • LH/FSH • Prolactin • LFT/U&Es • B-hCG • TFT • Estrogen • U/S-Mamogram Gynecomastia : Treatment • Conservative –Reassurance • Treatment of cause • Tamoxifen • Surgery Quiz Quiz • Which organ produces testosterone • In Men – Only testes • In women - None • GnRH secretion is normally continuous • LH and FSH is involved in testosterone production • Most testosterone is bound to protein (albumin/SHBG) Quiz • High LH/FSH and Low testosterone • Low LH/FSH and testosterone • What other investigation • Treatment Quiz • What do you mean by gynaecomastia • Uncommon to have gynaecomastia during puberty • Gynaecomastia during puberty Is it self limiting • How would you investigate • What are the treatment options Thank you