1. THE REPRODUCTIVE SYSTEM

2. In the male, the testis has two principal functions:1
Synthesis of testosterone by the interstitial Leydig cells controlled by luteinising hormone (LH) 2
Spermatogenesis by Sertoli cells under the control of follicle-stimulating hormone (FSH).
Negative feedback suppression of LH is mediated principally by testosterone, while inhibin suppresses FSH.

3. In the female, sex hormones vary during the menstrual cycle
FSH produces growth and development of ovarian follicles during the first 14 days.
This leads to a gradual increase in oestradiol production which initially suppresses FSH secretion (negative feedback) but then, above a certain level, stimulates an increase in the frequency and amplitude of gonadotrophin- releasing hormone (GnRH) pulses, resulting in a marked increase in LH secretion (positive feedback).
This LH surge induces ovulation.
The follicle then differentiates into a corpus luteum which secretes progesterone. Withdrawal of progesterone results in menstrual bleeding

5. The cessation of menstruation (the menopause) occurs in developed countries at a median age of 50.8 yrs.
In the 5 yrs before there is an increase in the number of anovulatory cycles, referred to as the climacteric. Oestrogen and inhibin secretion falls, resulting in increased pituitary secretion of LH and FSH.

6. DELAYED PUBERTY
Genetic factors influence the timing of the onset of puberty, although body weight acts as a trigger. Puberty may be considered delayed if it has not begun by a chronological age >2.5 standard deviations (SD) above the national average (>14 in boys, >13 in girls in the UK).
The key issue is to determine whether the delay in puberty is because the ‘clock is running slow’ (constitutional delay) or because of pathology in the hypothalamus/ pituitary (hypogonadotrophic hypogonadism) or the gonads (hypergonadotrophic hypogonadism).

7. DELAYED PUBERTY
The key issue is to determine whether the delay in puberty is because the ‘clock is running slow’ (constitutional delay) or because of pathology in the hypothalamus/ pituitary (hypogonadotrophic hypogonadism) or the gonads (hypergonadotrophic hypogonadism).

8. CAUSES OF DELAYED PUBERTY AND HYPOGONADISM
Constitutional delay
Hypogonadotrophic hypogonadism
Structural hypothalamic/pituitary disease
Functional gonadotrophin deficiency
Chronic systemic illness (e.g. asthma, coeliac disease, cystic fi brosis)
Psychological stress, anorexia nervosa, excessive exercise
Endocrine disease:
hyperprolactinaemia,
Cushing’s,
hypothyroidism
Isolated gonadotrophin deficiency (Kallmann’s)
Hypergonadotrophic hypogonadism
Chemotherapy/radiotherapy to gonads
Gonadal trauma/surgery,
cryptorchidism
Autoimmune gonadal failure
Mumps,
TB,
haemochromatosis
Klinefelter’s/Turner’s syndrome

9. Constitutional delay
This should be considered a normal variant and is the most common cause of delayed puberty.
Affected children are typically shorter than their peers throughout childhood.
There is often a family history and bone age is lower than chronological age.
Puberty will start spontaneously, but prolonged delay can have significant psychological consequences

10. Hypogonadotrophic hypogonadism:
This may be due to structural, infl ammatory or infi ltrative disorders of the pituitary/hypothalamus (p. 373). Other pituitary hormones are likely to be defi cient. ‘Functional’ gonadotrophin defi ciency is caused by a variety of factors (see Box 10.8). Isolated gonadotrophin defi ciency is due to a genetic abnormality affecting GnRH or gonadotrophin synthesis. The most common form is Kallmann’s syndrome which is also associated with olfactory bulb agenesis, resulting in anosmia. If left untreated, the epiphyses fail to fuse, resulting in tall stature with disproportionately long arms and legs (eunuchoid habitus). Cryptorchidism (undescended testes) and gynaecomastia are seen in all forms of hypogonadotrophic hypogonadism

11. Hypergonadotrophic hypogonadism:
Hypergonadotrophic hypogonadism associated with delayed puberty is usually due to sex chromosome abnormalities (Klinefelter’s/Turner’s syndromes, p. 356). Other causes of primary gonadal failure are shown in Box 10.8.

12. Investigations • Height should be plotted on centile charts.
Key measurements are LH/ FSH, testosterone, oestradiol, FBC, renal, liver and thyroid function, and coeliac disease autoantibodies.
Chromosome analysis is performed if gonadotrophin concentrations are elevated.
• If gonadotrophin concentrations are low, the differential diagnosis lies between constitutional delay and hypogonadotrophic hypogonadism.
A wrist X-ray allows estimation of bone age
Neuroimaging is required in hypogonadotrophic hypogonadism.

13. Management
Puberty can be induced using low doses of oestrogen or testosterone
Higher doses carry a risk of early fusion of epiphyses and therefore therapy should be administered and monitored by a specialist.
In constitutional delay, therapy is withdrawn once puberty is established.
In other cases, hormone doses are gradually increased during puberty and full adult replacement doses given when development is complete.

14. Decreased frequency of shaving
MALE HYPOGONADISM
The clinical features of both hypo- and hypergonadotrophic hypogonadism in men include:
Loss of libido
Lethargy
Muscle weakness
Decreased frequency of shaving
Gynecomastia
Infertility
Delayed puberty
Erectile dysfunction

15. Management
Testosterone replacement is indicated to prevent osteoporosis and to restore muscle power and libido.
Testosterone administration should be avoided in prostatic carcinoma. In men over 50, prostate-specifi c antigen (PSA) should be monitored
Men with hypogonadotrophic hypogonadism who wish fertility are usually given injections of hCG.
Extraction of sperm from the epididymis, in vitro fertilisation and intracytoplasmic sperm injection (ICSI) are used in primary testicular disease

16. GYNAECOMASTIA
Gynaecomastia is the presence of glandular breast tissue in males, resulting from an imbalance between androgen and oestrogen activity (androgen defi ciency or oestrogen excess).
Causes are listed in the next slide.
The most common are physiological, i.e. in the newborn baby (maternal oestrogens), in pubertal boys (oestradiol concentrations reach adult levels before testosterone) and in elderly men (↓testosterone concentrations). Gynaecomastia is often asymmetrical.

17. CAUSES OF GYNAECOMASTIA
Idiopathic
Physiological
Drug-induced: cimetidine, digoxin, anti-androgens (cyproterone acetate, spironolactone)
Hypogonadism
Androgen resistance syndromes
Oestrogen excess: liver failure (impaired steroid metabolism), oestrogen secreting tumor (e.g. testis), hCG-secreting tumor (e.g. testis, lung)

18. Palpation may allow breast tissue to be distinguished from adipose tissue observed in obesity. If a clinical distinction between gynaecomastia and adipose tissue cannot be made, then USS or mammography is required.
• The testes should be examined for cryptorchidism, atrophy or a tumour.
Testosterone, LH, FSH, oestradiol, prolactin and hCG should be measured. Elevated oestrogen concentrations are found in testicular tumours and hCG- producing neoplasms.
The underlying cause should be addressed, e.g. changing drug treatments, excision of tumour
In physiological gynaecomastia, reassurance is usually suffi cient but if the condition is associated with signifi cant psychological distress, surgical excision may be justifi ed.
• Androgen replacement improves gynaecomastia in hypogonadal males.

19. HIRSUTISM
Hirsutism refers to the excessive growth of thick terminal hair in an androgen- dependent distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm). It should be distinguished from hypertrichosis, which is generalised excessive growth of vellus hair.

20. Important observations are a drug and menstrual history, BMI, BP, examination for virilisation (clitoromegaly, deep voice, male-pattern balding, breast atrophy) and associated features, e.g. Cushing’s syndrome.
Recent hirsutism associated with virilisation is suggestive of an androgen- secreting tumour.
Testosterone, prolactin, LH and FSH should be measured. If testosterone levels are over twice the upper limit of the normal female range, especially with ↓LH and ↓FSH, then causes other than idiopathic hirsutism and PCOS are more likely.