Endocrinology

Lec 6

Dr Yasameen Alsaffar
Reproductive system
Female reproductive system
Normal menstrual cycle:
In the female, the physiology varies during the normal menstrual cycle. FSH stimulates growth and development of ovarian follicles during the first 14 days after the menses. This leads to a gradual increase in oestradiol production from granulosa cells, which initially suppresses FSH secretion (negative feedback) but then, above a certain level, stimulates an increase in both the frequency and amplitude of gonadotrophin-releasing hormone (GnRH) pulses, resulting in a marked increase in LH secretion (positive feedback). The mid-cycle ‘surge’ of LH induces ovulation. After release of the ovum, the follicle differentiates into a corpus luteum, which secretes progesterone. Unless pregnancy occurs during the cycle, the corpus luteum regresses and the fall in progesterone levels results in menstrual bleeding. Circulating levels of oestrogen and progesterone in pre-menopausal women are, therefore, critically dependent on the time of the cycle. The most useful ‘test’ of ovarian function is a careful menstrual history: if menses are regular, measurement of gonadotrophins and oestrogen is not necessary. In addition, ovulation can be confirmed by measuring plasma progesterone levels during the luteal phase (‘day 21 progesterone’)
Cessation of menstruation (the menopause) occurs at an average age of approximately 50 years in developed countries. In the 5 years before, there is a gradual increase in the number of anovulatory cycles and this is referred to as the climacteric. Oestrogen and inhibin secretion falls and negative feedback results in increased pituitary secretion of LH and FSH (both typically to levels above 30 IU/L (3.3 μg/L)). See the following figure

Classification of reproductive system diseases

Primary
Secondary
Hormone excess
Polycystic ovarian syndrome
Granulosa cell tumour
Leydig cell tumour Teratoma
Pituitary
gonadotrophinoma
Hormone deficiency
Menopause Hypogonadism
Turner’s syndrome Klinefelter’s syndrome
Hypopituitarism
Kallmann’s syndrome (isolated GnRH deficiency)
Severe systemic illness, including anorexia nervosa
Hormone hypersensitivity Idiopathic hirsutism
Hormone resistance Androgen resistance syndromes Complete (‘testicular feminisation’) Partial (Reifenstein’s syndrome) 5α-reductase type 2 deficiency
Non-functioning tumours
Ovarian cysts
Carcinoma
Teratoma
Seminoma


Delayed puberty:
Puberty is considered to be delayed if the onset of the physical features of sexual maturation has not occurred by a chronological age that is 2.5 standard deviations (SD) above the national average. In the UK, this is by the age of 14 in boys and 13 in girls. Genetic factors have a major influence in determining the timing of the onset of puberty, such that the age of menarche (the onset of menstruation) is often comparable within sibling and mother–daughter pairs and within ethnic groups. However, because there is also a threshold for body weight that acts as a trigger for normal puberty, the onset of puberty can be influenced by other factors including nutritional status and chronic illness.
Causes:
1. Constitutional delay
2. Hypogonadotrophic hypogonadism
A/Structural hypothalamic/pituitary disease
B/Functional gonadotrophin deficiency:
Chronic systemic illness (e.g. asthma, malabsorption, coeliac disease, cystic fibrosis, renal failure)
Psychological stress
Anorexia nervosa
Excessive physical exercise
Hyperprolactinaemia
Other endocrine disease (e.g. Cushing’s syndrome, primary hypothyroidism)
C/Isolated gonadotrophin deficiency (Kallmann’s syndrome)
3. Hypergonadotrophic hypogonadism
• Acquired gonadal damage: Chemotherapy/radiotherapy to gonads Trauma/surgery to gonads
Autoimmune gonadal failure
Mumps orchitis
Tuberculosis
Haemochromatosis
4. Developmental/congenital gonadal disorders:
Steroid biosynthetic defects
Anorchidism/cryptorchidism in males
Klinefelter’s syndrome (47XXY, male phenotype)
Turner’s syndrome (45XO, female phenotype)
Investigations
Key measurements are LH and FSH, oestradiol (in girls).
Chromosome analysis should be performed if gonadotrophin concentrations are elevated.
If gonadotrophin concentrations are low, then the differential diagnosis lies between constitutional delay and hypogonadotrophic hypogonadism.
A plain X-ray of the wrist and hand may be compared with a set of standard films to obtain a bone age.
Full blood count, renal function, liver function, thyroid function and coeliac disease autoantibodies should be measured, but further tests may be unnecessary if the blood tests are normal and the child has all the clinical features of constitutional delay.
If hypogonadotrophic hypogonadism is suspected, neuroimaging and further investigations are required.
Management
Puberty can be induced using low doses of oral oestrogen in girls (e.g. ethinylestradiol 2 μg daily)
Hirsutism: refers to the excessive growth of terminal hair (the thick, pigmented hair usually associated with the adult male chest) in an androgen-dependent distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm) and is one of the most common presentations of endocrine disease. It should be distinguished from hypertrichosis, which is generalised excessive growth of vellus hair (the thin, non-pigmented hair that is typically found all over the body from childhood onwards).


Approach to patients with hirsuitism
Causes
Clinical features
Ix
Rx
Idiopathic
Often familial Mediterranean or Asian background
Normal
Cosmetic
Antiandrogens
PCOS
Obesity Oligomenorrhoea or secondary amenorrhoea Infertility
LH:FSH ratio > 2.5:1
Minor elevation of androgens
Mild hyperprolactinaemia
Wt loss
Cosmetic measures
Anti-androgens (Metformin, glitazones may be useful
Congenital adrenal hyperplasia (95% 21-hydroxylase deficiency
Pigmentation History of salt-wasting in childhood, ambiguous genitalia, or adrenal crisis when stressed Jewish background
Elevated androgens* that suppress with dexamethasone Abnormal rise in 17-OH-progesterone with ACTH
Glucocorticoid replacement
Exogenous androgen administration
Athletes Virilisation
Low LH and FSH Analysis of urinary androgens may detect drug of misuse
Stop misuse
Androgen-secreting tumour of ovary or adrenal cortex
Rapid onset Virilisation: clitoromegaly, deep voice, balding, breast atrophy
high androgens* that do not suppress with dexamethasone Low LH and FSH CT or MRI usually demonstrates a tumour
Sx
Cushing’s syndrome
S&S of Cushing’s
Ix of Cushin’s
Rx of Cushing’s


Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) affects up to 10% of women of reproductive age. It is a heterogeneous disorder often associated with obesity, for which the primary cause remains uncertain. Genetic factors probably play a role, since PCOS often affects several family members. The severity and clinical features of PCOS vary markedly between individual patients but diagnosis is usually made during the investigation of hirsutism or amenorrhoea/oligomenorrhoea . Infertility may also be present. There is no universally accepted definition but it has been recommended that a diagnosis of PCOS requires the presence of two of the following three features:
• Menstrual irregularity
• Clinical or biochemical androgen excess
• Multiple cysts in the ovaries (most readily detected by transvaginal ultrasound)
Women with PCOS are at increased risk of glucose intolerance and some authorities recommend screening for type 2 diabetes and other cardiovascular risk factors associated with the metabolic syndrome.
Mechanisms*
Manifestations
Pituitary dysfunction
High serum LH High serum prolactin
Anovulatory menstrual cycles
Oligomenorrhoea
Secondary amenorrhoea
Cystic ovaries
Infertility
Androgen excess
Hirsutism
Acne

Obesity

Hyperglycaemia
Elevated oestrogens
Insulin resistance
Dyslipidaemia
Hypertension


Management
Wt loss
Metformin
Antiandrogens
Estrogen
Local measures