PRIMARY AND SECONDARY HYPOGONADISM-1.pptx

Hypogonadism is amongst the most tricky causes of infertility that the general public is not well informed about. This material helps to educate people who are unaware.

1. PRIMARY AND SECONDARY HYPOGONADISM MOHAMMED IBRAHIM JUNIOR UJ/2017/MD/0549 05/02/2023

2. OUTLINE INTRODUCTION DEFINITION EPIDEMIOLOGY TYPES PRIMARY HYPOGONADISM Definition Aetiology Pathophysiology SECONDARY HYPOGONADISM Definition Aetiology Pathophysiology CLINICAL FEATURES INVESTIGATIONS TREATMENT CONCLUSION REFERENCES 2

3. INTRODUCTION Reproductive endocrinology encompasses the hormones of the hypothalamic-pituitary-gonadal axis, as well as the adrenal glands including gonadotropin-releasing hormone ( GnRH ), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and a multitude of sex steroids. The sex steroids are synthesized by the ovaries, testes, and adrenal glands and are responsible for the manifestation of primary and secondary sex characteristics . 3

4. … INTRODUCTION CONT’D Production of a man’s testosterone and a woman’s estrogen are suppressed or completely inhibited in hypogonadism  Morbidity for men and women with hypogonadism includes infertility and an increased risk of osteoporosis; there is no increase in mortality . 4

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7. DEFINITION Hypogonadism refers to a condition where the body produces insufficient amounts of sex hormones, particularly testosterone in males and estrogen in females. 7

8. EPIDEMIOLOGY No racial predilection has been described. Hypergonadotropic hypogonadism is more common in males than in females because the incidence of Klinefelter syndrome (the most common cause of primary hypogonadism in males) is higher than the incidence of Turner syndrome (the most common cause of hypogonadism in females). Incidence of hypogonadotropic hypogonadism is equal in males and females. 8

9. TYPES OF HYPOGONADISM Primary hypogonadism ( hypergonadotropic hypogonadism) Secondary hypogonadism (hypogonadotropic hypogonadism) 9

10. Primary hypogonadism ( hypergonadotropic hypogonadism ) Primary hypogonadism occurs when there is a dysfunction in the gonads, which are the reproductive organs responsible for producing sex hormones. In males, the gonads are the testes, and in females, they are the ovaries. 10

11. AETIOLOGY Causes of hypergonadotropic hypogonadism (primary hypogonadism) in males include the following: Klinefelter’s syndrome (47,XXY) LH or FSH receptor mutations Primary testicular failure, e.g. chemotherapy, mumps orchitis , trauma, radiation, autoimmune , LH resistance, anorchism /cryptorchidism, testicular biosynthetic defects- 17β- hydroxylase dehydrogenase deficiency, 5 α- reductase deficiency, 17-hydroxylase deficiency 11

12. Causes of hypergonadotropic hypogonadism (primary hypogonadism) in females include the following: Galactosemia Glycoprotein syndrome type 1 FSH-receptor gene mutations LH/human chorionic gonadotropin ( hCG ) resistance Polycystic ovarian disease Noonan syndrome 12 Turner syndrome Inactivating mutations XX and XY gonadal dysgenesis Premature menopause Radiation therapy Chemotherapy Autoimmune oophoritis Resistant ovary

13. PATHOPHYSIOLOGY The gonads function as part of the hypothalamic-pituitary-gonadal axis. A hypothalamic pulse generator resides in the arcuate nucleus, which releases luteinizing hormone (LH)-releasing hormone (LHRH), which is also termed gonadotropin-releasing hormone ( GnRH ), into the hypothalamic-pituitary portal system. Data suggest that a gene named KISS is important in the development of the LHRH-secreting cells. 13

14. In response to these pulses of LHRH, the anterior pituitary secretes FSH and LH, which, in turn, stimulate gonadal activity. The increase in gonadal hormones results in lowered FSH and LH secretion at the pituitary level, completing the feedback loop. In the testes, LH stimulates Leydig cells to secrete testosterone , whereas FSH is necessary for tubular growth. In the ovaries, LH acts on theca and interstitial cells to produce progestins and androgens , and FSH acts on granulosa cells to stimulate aromatization of these precursor steroids to estrogen . 14

15. 15 Genetic factors: in cases of genetic conditions e.g., Klinefelter syndrome in males and Turner’s syndrome in females (with 47,XXY and 45,XO chromosomal abnormalities respectively), which affect gonadal development and function. Infections and inflammation: infections such as mumps can cause inflammation of the testicles ( orchitis ), or ovaries, disrupting normal tissue function and hormone production. Autoimmune disorders : autoimmune reactions can lead to the immune system mistakenly attacking and damaging gonadal tissues, impairing hormone synthesis.

16. 16 Tumours : tumours in the gonads may interfere with normal cellular processes, either directly affecting hormone-producing cells or disrupting the organ’s overall function Trauma: physical trauma to the testes or ovaries can result in structural damage, impacting their ability to produce hormones. Toxins and environmental factors: exposure to certain toxins or environmental factors like radiation might contribute to gonadal damage and dysfunction.

17. Secondary hypogonadism ( hypogonadotropic hypogonadism) [low FSH/LH and low testosterone (males) or oestrogen (females)] Secondary hypogonadism is a condition characterized by impaired sex hormone production by the testes or ovaries as a result of a defect from the higher centers ( i.e hypothalamus and/or pituitary gland) 17

18. AETIOLOGY Genetic causes Kallmann’s syndrome (anosmia and GnRH deficiency) GnRH receptor mutations Isolated LH or FSH deficiency PROP1 gene mutations that lead to absence of some pituitary hormones Secondary causes Cerebral tumours , e.g. craniopharyngioma , pituitary tumour , astrocytoma Head trauma Cerebral infections, vascular abnormalities, cerebral radiation Chronic systemic disease and undernutrition Exercise-induced amenorrhoea ( females) Hyperprolactinaemia Miscellaneous causes Morbid obesity Marijuana or opiate use Prader –Willi syndrome Laurence–Moon ( Bardet – Biedl ) syndrome 18

19. PATHOPHYSIOLOGY Hypogonadotropic hypogonadism may result from failure of the hypothalamic LHRH pulse generator or from inability of the pituitary to respond with secretion of LH and FSH. Hypogonadotropic hypogonadism is most commonly observed as one aspect of multiple pituitary hormone deficiencies resulting from malformations ( eg , septooptic dysplasia, other midline defects) or lesions of the pituitary that are acquired postnatally . 19

20. 20 Normosmic hypogonadotropic hypogonadism, in which the sense of smell is not disrupted, has been associated with mutations in GNRH1, KISS1R , and GNRHR genes. Although their exact functions are unclear, the genes TAC3 and TACR3 have also been associated with normosmic hypogonadotropic hypogonadism. Kallmann syndrome ( anosmic hypogonadotropic hypogonadism) has been associated with mutations in KAL1, FGFR1, FGF8, PROK2, and PROKR2 genes. The relationship with Kallmann syndrome is thought to be because these genes are all related to the development and migration of GnRH neurons.

21. CLINICAL FEATURES clinical features of hypogonadism in males include: Specific issues include the presence of developmental anomalies associated with the genital system ( eg , hypospadias , micropenis , cryptorchidism ) Reduced libido Erectile dysfunction Generalized feminization ( e.g female pattern of hair distribution, gynaecomastia ) Fatigue and low energy Infertility Decreased muscle mass Increased body fat 21

22. clinical features of hypogonadism in females include: Absent or irregular menstrual cycles Reduced libido Virilism hirsuitism Hot flashes Vaginal dryness Bone density loss (osteoporosis) 22

23. INVESTIGATIONS A careful clinical history, including medications , and physical examination can be useful . Measurement of plasma LH, FSH, TSH, prolactin , oestradiol , testosterone and SHBG may reveal a diagnosis. If intersex conditions are sought, karyotyping may be useful 23

24. 24 Gonadotrophin-releasing hormone test: The test is used to diagnose hypothalamic–pituitary disease in precocious and delayed puberty with low basal gonadotrophin concentrations. Human chorionic gonadotrophin stimulation test: Human chorionic gonadotrophin shares a common subunit with LH and stimulates testicular Leydig cells to release androgens. It has a long half-life and elicits a rise in plasma testosterone after 72–120 h . The test may be indicated in the following situations: to confirm the presence of testes, in infants with ambiguous genitalia and palpable gonads, in males with delayed puberty, in some cases of undescended testicles.

25. 25 Imaging studies: MRI OR CT scans may be performed to evaluate the hypothalamus and pituitary gland for any structural abnormalities such as tumours Bone Density Test (DEXA Scan): Especially in women, assessing bone density can provide insights into the impact of hormonal deficiencies on bone health.

26. TREATMENT hypogonadism are typically treated with sex steroid replacement. The goals of treatment are: To promote the development of and maintain secondary sexual characteristics and normal sexual function To build and sustain normal bone and muscle mass To assist in the proper psychosocial adjustment of adolescents with hypogonadism Fertility options can be explored in consultation with a reproductive endocrinologist or urologist. Pulsatile LHRH or gonadotropin therapy can induce fertility in individuals with hypogonadotropic hypogonadism. 26

27. 27 Testosterone Replacement Therapy (TRT): this involves administering testosterone to bring levels back to normal in males. (injections, patches, gels and pellets) Estrogen Replacement Therapy is often used to address low estrogen levels in women. (oral pills, patches, creams, or vaginal rings) Monitoring and adjustments: regular follow up is crucial to monitor hormone levels and adjust treatment as needed. This ensures that hormonal balance is maintained while minimizing potential risks.

28. 28 Bone health management: since estrogen plays a role in maintaining bone density, calcium and vit . D supplements, along with weight-bearing exercises may be recommended to support bone health. Fertility preservation: hCG or selective estrogen modulators might be considered to stimulate natural testosterone production in men. Conversely, gonadotropin therapy or IVF may be considered in women, depending on the specific hormonal imbalances Management of underlying conditions e.g pituitary tumours or other medical conditions is essential for comprehensive treatment

29. CONCLUSION Hypogonadism may occur at any age, however, consequences differ according to the age at onset: If hypogonadism occurs prenatally, sexual ambiguity may result If hypogonadism occurs before puberty, puberty does not progress. If hypogonadism occurs after puberty, infertility and sexual dysfunction results. 29

30. REFERENCES CLINICAL BIOCHEMISTRY & METABOLIC MEDICINE (MARTIN A. CROOK) LECTURE NOTE BY DR. LUCIUS IMOH HTTPS://EMEDICINE.MEDSCAPE.COM/ARTICLE/922038-CLINICAL?FORM=FPF#B1 30