FEMALE REPRODUCTION AND SEX

In the adult female higher brain centres impose a menstrual cycle of 28 days upon the activity of hypothalamic GnRH. Pulses of GnRH stimulate the release of pituitary LH and FSH. LH stimulates ovarian androgen production and FSH stimulates follicular development and aromatase activity (an enzyme required to convert ovarian androgens to oestrogens). Oestrogens are necessary for normal pubertal development and, together with progesterone, for mainte-nance of the menstrual cycle; they also have effects on a variety of tissues.

The menopause

The menopause, or cessation of periods, naturally occurs about the age of 45-55 years. During the late 40s, first FSH and then LH concentrations begin to rise, probably as a result of diminishing follicle supply. Oestrogen levels

Table 14.7 Causes of gynaecomastia
Physiological
Neonatal, resulting from the influence of maternal hormones
Pubertal
Old age
Deficient testosterone secretion
Any cause of hypogonadism (Table 14.6)
Oestrogen-producing tumours
Of the testis or adrenal gland
HCG-producing tumours
Of the testis or the lung
Drugs
Oestrogenic: oestrogens, digoxin, cannabis, diamorphine
Anti-androgens: spironolactone, cimetidine, cyproterone,
Others: gonadotrophins, cytotoxics
Other
Hyperthyroidism
Carcinoma of the breast
HCG, human chorionic gonadotrophin

fall and the cycle becomes disrupted. Menopause may also occur surgically, with radiotherapy to the ovaries and with ovarian disease (e.g. premature menopause in the 20s and 30s). Symptoms of the menopause are hot flushes, vaginal dryness and breast atrophy. There may also be vague symptoms of depression, loss of libido and weight gain. There is loss of bone density (osteoporosis) and the premenopausal protection against ischaemic heart disease disappears.

Oestrogen replacement is the most effective treatment available for the relief of menopausal symptoms and also reduces the risk of colorectal cancer and osteoporotic fractures. However, HRT increases the risk of breast cancer, coronary heart disease (CHD), stroke and venous thromboembolism. Oestro-gens, when given alone (without progestogens), increase the risk of endo-metrial cancer. The main indication for HRT is for control of menopausal symptoms with the lowest effective dose for the shortest time possible. It is not recommended purely for prevention of postmenopausal osteoporosis and bisphosphonates or selective oestrogen receptor modulators (SERMs), e.g. raloxifene are the preferred treatment. SERMs have the advantage of positive oestrogen effects on bone with no effect on oestrogen receptors of breast and uterus. HRT is used in premature ovarian failure (before age 40 years) when the benefits of treatment outweigh the risks. HRT is contraindicated in women with a history of thromboembolism, stroke, CHD or breast cancer.

Female hypogonadism and amenorrhoea

Amenorrhoea is the absence of menstruation. It is often physiological, e.g. during pregnancy and lactation, and after the menopause. Primary amenor-rhoea is failure to start spontaneous menstruation by the age of 16 years. Secondary amenorrhoea is the absence of menstruation for 3 months in a woman who has previously had menstrual cycles. In the female, hypogonad-ism almost always presents as amenorrhoea or oligomenorrhoea (fewer than nine menses per year). The other features of oestrogen deficiency include atrophy of the breasts and vagina, loss of pubic hair and osteoporosis.

Aetiology

The causes of amenorrhoea are listed in Table 14.8. Polycystic ovary syn-drome is the most common cause of oligomenorrhoea and amenorrhoea in clinical practice, though one should always consider pregnancy as a possible

Table 14.8 Pathological causes of amenorrhoea
Hypothalamic
GnRH deficiency (isolated or as part of Kallmann’s syndrome)*
Weight loss, physical exercise, stress
Post oral contraceptive therapy
Pituitary
Hyperprolactinaemia
Hypopituitarism
Gonadal
Polycystic ovary syndrome
Premature ovarian failure – autoimmune basis
Defective ovarian development (dysgenesis)*
Androgen-secreting ovarian tumours
Radiotherapy
Other diseases
Thyroid dysfunction
Cushing’s syndrome
Adrenal tumours
Severe illness
Uterine/vaginal abnormality
Imperforate hymen or absent uterus*
*Presents as primary amenorrhoea

cause. Severe weight loss (e.g. anorexia nervosa) has long been associated with amenorrhoea, but less severe forms of weight loss (by dieting and exercise) are a common cause of amenorrhoea caused by abnormal secretion of GnRH.

Investigations

The cause of amenorrhoea may be apparent after a full history and examina-tion. Basal levels of serum FSH, LH, oestrogen and prolactin will allow a distinction between primary gonadal and hypothalamic-pituitary causes. Further investigations, e.g. ultrasonography of the ovaries, laparoscopy and ovarian biopsy, pituitary MRI and measurement of serum testosterone, will depend on the probable site of the defect and the findings on clinical examination.

Management

Treatment is of the cause where possible, e.g. increase weight, treat hypo-thyroidism and hyperprolactinaemia. In patients where the underlying defect cannot be corrected, cyclical oestrogens are given to reverse the symptoms of oestrogen deficiency and prevent early osteoporosis. Patients with isolated GnRH deficiency or hypopituitarism are treated with human FSH/LH. The management of polycystic ovaries is discussed below.

Hirsutism and polycystic ovary syndrome (PCOS)

Hirsutism is excess hair growth in women in a male pattern (androgen dependent): beard area, abdominal wall, thigh, axilla and around the nipples. Hirsutism should be differentiated from hypertrichosis which is androgen independent and refers to a general increase in body hair; this can be racial (the Mediterranean and some Asian Indian subcontinent populations), caused by drugs (e.g. ciclosporin, minoxidil, phenytoin) or anorexia nervosa, or may be familial.

Hirsutism indicates increased androgen production by the ovaries or adrenal glands most commonly PCOS. Rarer causes are congenital adrenal hyperplasia, ovarian or adrenal androgen-secreting tumour, prolactinoma and Cushing's disease. Signs of virilization (clitoromegaly, recent-onset frontal balding, deepening of the voice and loss of female body shape) implies substantial androgen excess, and usually indicates a cause other than PCOS.

PCOS is one of the most common hormonal disorders affecting women. It is characterized by multiple small cysts within the ovary (which represent arrested follicular development) and by excess androgen production from the ovaries and, to a lesser extent, from the adrenals. PCOS is frequently associated with hyperinsulinaemia and insulin resistance and there is an increased frequency of type 2 diabetes mellitus. It is also associated with hypertension, hyperlipidaemia and increased cardiovascular disease. The precise mechanisms that link this syndrome remain to be elucidated, but may play a role in the causation of macrovascular disease in women.

Clinical features

Typically PCOS presents with amenorrhoea or oligomenorrhoea (menstrual cycles longer than 35 days or fewer than 10 periods a year), hirsutism and acne, usually beginning shortly after menarche. It is sometimes associated with marked obesity, but weight may be normal. Mild virilization occurs in severe cases.

Criteria for diagnosis

Diagnostic criteria for PCOS have been proposed by several groups. In the Rotterdam criteria the diagnosis of PCOS is made when two of the following three criteria are present and other differentials (androgen-secreting tumour, Cushing's syndrome, congenital adrenal hyperplasia) are excluded:

■ Menstrual irregularity (amenorrhoea or oligomenorrhoea) due to oligo-and/or anovulation.

■ Clinical (hirsutism, acne, frontal balding) or biochemical evidence of hyperandrogenism.

■ Polycystic ovaries (multiple cysts) on ultrasound examination.

Investigations and differential diagnosis

■ Sex hormones - serum total testosterone concentration may be normal in PCOS and fail to detect biochemical hyperandrogenism. This is because sex hormone binding globulin (which affects total testosterone concentra-tion) is suppressed leading to high free (i.e bioavailable) testosterone levels. Biochemical evidence of hyperandrogenism is demonstrated by a raised free androgen index (serum total testosterone/sex hormone binding globulin concentration) which is a measure of bioavailable testo-sterone. Total testosterone concentrations more than 1.5-2 times the upper limit of normal or a history of rapid virilisation are likely to be associated with an androgen secreting tumour of the ovaries or adrenal glands.

■ Serum prolactin is slightly elevated in PCOS but values more than 1.5-2 times the upper limit of normal suggest pituitary or hypothalamic disease.

■ Serum 17-hydroxyprogesterone is elevated in patients with non-classic congenital adrenal hyperplasia.

■ Transvaginal ultrasound gives good visualization of the ovaries.

Management

Local therapy for hirsutism Excess hair can be removed or disguised by shaving, bleaching and waxing.

Systemic therapy for hirsutism

■ Oestrogens, e.g. oral contraceptives, suppress ovarian androgen produc-tion and reduce free androgen by increasing sex hormone-binding globu-lin levels.

■ Cyproterone acetate and flutamide are both antiandrogens. The latter is less commonly used because of a high incidence of hepatic side-effects.

■ Spironolactone has antiandrogen activity.

■ Finasteride, a 5a-reductase inhibitor, inhibits dihydrotestosterone forma-tion in skin.

Treatment of menstrual disturbance Cyclical oestrogen/progesterone administration regulates the menstrual cycle in addition to improving hir-sutism. Metformin improves hyperinsulinaemia, regulates the menstrual cycle and helps weight loss.

Treatment for infertility Patients with PCOS who require induction of ovulation are treated with the anti-oestrogen, clomifene

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology



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