Reproductive system disorders
Disorders of sex development
Sex development begins in utero but continues
into young adulthood with the achievement of
sexual maturity and reproductive capability.
The early stages of sex development can be
divided into three major components:
• chromosomal sex
• gonadal sex (sex determination)
• phenotypic sex (sex differentiation)
Disorders of chromosomal sex
Disorders of chromosomal sex result from abnormalities in the
number or structure of the X or Y chromosomes.
Klinefelter Syndrome (47, XXY karyotype)
Clinical Features:
• small testes
• Infertility
• Gynecomastia
• eunuchoid proportions and poor virilization in
phenotypic males.
Klinefelter Syndrome (47, XXY
karyotype)
In addition to features of hypogonadism, patients
may have:
• intellectual dysfunction and behavioural
abnormalities that cause difficulty in social
interactions
• a predisposition to develop chronic bronchitis,
bronchiectasis and emphysema, germ cell
tumours (e.g. involving the mediastinum), breast
cancer (a 20 - fold increased risk), possibly non Hodgkin’s lymphoma, varicose veins, leg ulcers
and diabetes mellitus.
Treatment of KS
• Gynecomastia should be treated by surgical reduction if
it causes concern.
• Androgen supplementation improves virilization,
libido, energy, hypofibrinolysis, and bone
mineralization in underandrogenized men but may
occasionally worsen gynecomastia.
• Fertility has been achieved using in vitro fertilization in
men with oligospermia or with intracytoplasmic sperm
injection (ICSI) following retrieval of spermatozoa by
testicular sperm extraction techniques.
TURNER SYNDROME (GONADAL
DYSGENESIS; 45,X karyotype)
Clinical Features:
• bilateral streak gonads
• primary amenorrhea
• short stature
• multiple congenital anomalies in phenotypic
females.
TURNER SYNDROME
Treatment of Turner Syndrome
The treatment of short stature in children with TS
remains a challenge, as untreated final height rarely
exceeds 150 cm. High-dose recombinant growth
hormone stimulates growth rate in children with TS
and may be used alone or in combination with low
doses of the anabolic steroid oxandrolone.
Girls with evidence of gonadal failure require
estrogen replacement to induce breast and uterine
development, to support growth, and to maintain
bone mineralization.
Male hypogonadism
Male hypogonadism is a syndrome of decreased
testosterone production, sperm production or
both.
Male hypogonadism may result from disease of
the testes (primary hypogonadism) or disease
of the pituitary or hypothalamus (secondary
hypogonadism).
Aetiology
Primary
Congenital causes
• Klinefelter’s syndrome and other chromosomal abnormalities
• Cryptorchidism
Acquired causes
• Infections (e.g. mumps orchitis)
• Testicular trauma or torsion
• Drugs, e.g. chemotherapy, ketoconazole, sulfasalazine, excess alcohol
• Radiotherapy
• Autoimmune damage
• Chronic illnesses
• Rare causes: mutations in genes encoding enzymes necessary for
testosterone synthesis, mutations in the gene encoding the follicle stimulating hormone receptor, myotonic dystrophy
Aetiology
Secondary
Congenital causes
• Gonadotropin-releasing hormone deficiency (Kallmann’s syndrome)
Acquired causes
• Pituitary or hypothalamic disease (pituitary adenomas, cysts, other
tumours, surgery, head trauma, infections, infarction, infiltrative
disorders)
• Suppression of gonadotropins (chronic systemic illness, diabetes
mellitus, hyperprolactinaemia, androgen excess (e.g. anabolic
steroids), cortisol excess (exogenous or Cushing’s syndrome),
oestrogen excess (e.g. produced by a testicular tumour),
gonadotrophin - releasing hormone analogues, opiates)
• Rare causes: Laurence – Moon – Biedl syndrome, Prader–Willi
syndrome, etc.
Primary hypogonadism
In primary hypogonadism, reduced testosterone
levels result in elevated gonadotrophin levels
(due to a reduced negative feedback effect of
testosterone on the hypothalamus and pituitary).
Thus primary hypogonadism is also known
as hypergonadotrophic hypogonadism. Primary
hypogonadism may be congenital or acquired.
Secondary hypogonadism
Secondary (or hypogonadotrophic)
hypogonadism is due to impaired secretion of
hypothalamic GnRH or pituitary gonadotrophins.
Clinical signs of hypogonadism
Hypogonadism occurring before onset of puberty
• Testes < 5 mL
• Penis < 5 cm long
• Reduced pubic, axillary and facial hair
• Gynaecomastia
• Eunuchoid proportions: arm span > height, lower
segment > upper segment (due to delayed fusion of the
epiphyses and continued growth of the long bones)
• Features of the underlying cause, e.g. cryptorchidism,
anosmia (Kallmann’s syndrome)
Clinical signs of hypogonadism
Hypogonadism occurring after puberty
• Testes soft, < 15 mL
• Penis normal length (> 5 cm) and width (> 3 cm)
• Reduced pubic, axillary and facial hair
• Gynaecomastia
• Normal skeletal proportions
• Fine perioral wrinkles
• Features of the underlying cause, e.g. visual field
defects due to a pituitary tumour, signs of
systemic/chronic illness
Investigations
The diagnosis of hypogonadism can be confirmed
by finding low serum testosterone and/or decreased
sperm in the semen.
Measurement of the serum total testosterone
concentration is usually an accurate reflection of
testosterone secretion. Testosterone exhibits a
diurnal variation, with maximum levels at about 8
a.m. and lower levels in the evening. Thus
testosterone levels should be measured at 8 a.m. If a
single testosterone value is low or borderline low, it
should be repeated once or twice.
Investigations
In a hypogonadal patient (with low serum
testosterone and/or a subnormal sperm count):
• high LH and FSH concentrations indicate
testicular damage (primary hypogonadism)
• low or inappropriately normal LH and FSH
levels suggest pituitary or hypothalamic
disease (secondary hypogonadism).
Investigations
Magnetic resonance imaging (MRI) of the
hypothalamic – pituitary area should be
performed if the patient has other pituitary
hormonal abnormalities, headache or visual field
defects.
Treatment
Treatment should be directed at any underlying
disorders. The aim of therapy is to relieve the
symptoms and to preserve bone density. Boys who
have not gone through puberty are started on low
doses of testosterone, which are gradually increased.
In symptomatic men with a total testosterone of
consistently less than 8 nmol/L, testosterone
replacement therapy may be started if there are no
contraindications. Those with testosterone levels of
8 – 10 nmol/L require careful individual evaluation.
Gynaecomastia
Gynaecomastia is a benign proliferation of the
glandular tissue of the male breast. It is usually
bilateral but may be unilateral.
Epidemiology
Gynaecomastia is common in infancy, adolescence
and elderly men. A total of 60 – 90% of infants may
have transient gynaecomastia (for 2 – 3 weeks) due to
the high oestrogen levels in pregnancy. The second
peak of gynaecomastia occurs during puberty and
affects about 65% of boys. Almost all cases regress
spontaneously. The third peak of gynaecomastia
occurs in 25 – 65% of middle - aged and elderly men,
with the highest prevalence at 50 – 80 years.
Aetiology
Oestrogens stimulate ductal epithelial growth and proliferation of
the periductal fibroblasts.
Causes of gynaecomastia
Physiological
• Puberty, persistent pubertal (25% of cases), elderly
Drugs (10 – 25%)
• Oestrogens, antiandrogens, spironolactone (antiandrogenic effects),
cimetidine, nifedipine, herbal products/oils
Hypogonadism (primary 8%, secondary 2%)
• Reduced serum testosterone production
Chronic liver disease (8%)
• Enhanced aromatization (many patients are also on spironolactone)
• Chronic renal failure (1%)
• Reduced serum testosterone due to Leydig cell dysfunction
Thyrotoxicosis (1.5%)
• Enhanced aromatization
Aetiology
Tumours
• Testicular germ cell tumours secrete human chorionic gonadotrophin
(hCG) resulting in enhanced aromatization
• Testicular Leydig cell tumours secrete increased oestradiol
• Other hCG - secreting tumours, e.g. lung, stomach, renal cell and
liver
• Oestrogen - secreting adrenal tumours
No detectable abnormality (25%)
Rare causes
• Aromatase excess syndrome — rare autosomal dominant disorder of
ncreased aromatase activity
• Androgen insensitivity syndrome (testicular feminization) due to
defective/absent androgen receptor in the target tissues. Thus
patients are genotypic males but appear to be phenotypic females.
Clinical presentations
Gynaecomastia (enlargement of the glandular tissue) should be
differentiated from pseudogynaecomastia (excessive adipose
tissue often seen in obese men) and breast cancer. Ask the
patient to lie on his back with his hands behind his head. Place
your thumb and forefinger on each side of the breast and
slowly bring them together toward the nipple. In
gynaecomastia, a rubbery/firm disk of glandular tissue (at least
0.5 cm in diameter) will be felt extending concentrically from
the nipple. In pseudogynaecomastia, the fi ngers will not meet
any resistance until they reach the nipple. Breast cancer tends
to be eccentrically positioned (rather than symmetrical to the
nipple), tends to be firm to hard in texture, and may be
associated with skin dimpling, nipple retraction, discharge and
axillary lymphadenopathy.
Investigation of gynaecomastia
In adolescent boys, gynaecomastia is almost
always due to pubertal gynaecomastia and often
resolves spontaneously.
Asymptomatic gynaecomastia that is discovered
during a physical examination in a patient who
does not have one of the possible causative
conditions should be reevaluated in 6 months.
Investigation of gynaecomastia
Serum hCG, luteinizing hormone (LH),
testosterone, oestradiol, free thyroxine (T 4 ) and
thyroid - stimulating hormone (TSH) should be
measured, particularly if the gynaecomastia is of
recent onset or painful.
Investigation of gynaecomastia
• If hCG is elevated, a testicular ultrasound scan should be performed to look
for a testicular germ cell tumour. If testicular ultrasound is normal, a chest
radiograph and abdominal computed tomography (CT) should be done to
look for an hCG - secreting tumour.
• If testosterone is low and LH levels are increased , the diagnosis is primary
hypogonadism.
• If testosterone is low and LH levels are low or inappropriately normal, the
diagnosis is secondary hypogonadism. Serum prolactin should be measured
and magnetic resonance imaging (MRI) of the pituitary should be
performed.
• If free T4 levels are high and TSH is suppressed , the diagnosis is
thyrotoxicosis.
• If the oestradiol levels are increased and LH levels are low or normal,
testicular ultrasound should be performed to look for a Leydig or Sertoli
cell tumour. If the testicular ultrasound is normal, adrenal imaging
(CT/MRI) should be performed to look for an adrenal tumour. If the
imaging is normal, increased extraglandular aromatase activity is likely.
If all tests are normal, the diagnosis is “idiopathic gynaecomastia”.
Investigation of gynaecomastia
Treatment
The treatment of gynaecomastia depends on its cause, its
severity, the presence of tenderness and its duration.
Most adolescents with gynaecomastia should be followed up
and re - evaluated every 3 – 6 months. Gynaecomastia usually
resolves spontaneously within 6 months to 2 years.
In boys with severe gynaecomastia causing substantial
tenderness and/or embarrassment, a 3 - month trial of
tamoxifen (10 mg twice a day) may be considered. Patients
and parents should be told that these drugs are not approved
for this purpose.
Treatment
Men with an identifiable cause should be followed up and re - evaluated after
the possible cause has
been treated.
● Men with no identifiable cause and tender gynaecomastia persisting for
longer than 3 months may be treated with a 3 – 6 - month trial of tamoxifen
(10 mg twice daily). Patients should be told that tamoxifen is not approved for
this purpose.
● Men with persistent gynaecomastia ( > 1 – 2 years) who find it
psychologically troubling should be offered surgery, as the breast tissue has
probably become fibrotic and medical therapy is unlikely to be
effective.
● Men with advanced prostate cancer who are on antiandrogens may be given
tamoxifen to reduce the risk of developing gynaecomastia. Prophylactic
radiation is also an alternative. Tamoxifen may be also be tried in men who
have already developed gynaecomastia on antiandrogen therapy.
Hirsutism
Excessive male-pattern hair growth, which affects
approximately 10% of women.
Hirsutism is often idiopathic but may be caused by
conditions associated with androgen excess, such
as polycystic ovarian syndrome (PCOS) or
congenital adrenal hyperplasia. Cutaneous
manifestations commonly associated with hirsutism
include acne and male-pattern balding (androgenic
alopecia).
Virilization
Virilization refers to a condition in which
androgen levels are sufficiently high to cause
additional signs and symptoms such as seepening
of the voice, breast atrophy, increased muscle
bulk, clitoromegaly, and increased libido;
virilization is an ominous sign that suggests the
possibility of an ovarian or adrenal neoplasm.
Hirsutism
Historic elements relevant to the assessment of
hirsutism include the age of onset and rate of
progression of hair growth and associated
symptoms or signs (e.g., acne).
Hirsutism scoring scale
of Ferriman and
Gallwey
The nine body areas
possessing androgensensitive areas are graded
from 0 (no terminal hair)
to 4 (frankly virile) to
obtain a total score. A
normal hirsutism score is
less than 8.
Treatment of hirsutism
Treatment of hirsutism may be accomplished
pharmacologically or by mechanical means of hair removal.
Nonpharmacologic treatments should be considered in all
patients, either as the only treatment or as an adjunct to drug
therapy.
Pharmacologic therapy is directed at interrupting one or more
of the steps in the pathway of androgen synthesis and action.
Combination estrogen-progestin therapy, in the form of an oral
contraceptive, is usually the first-line endocrine treatment for
hirsutism and acne, after cosmetic and dermatologic
management (oral contraceptives are contraindicated in
women with a history of thromboembolic disease or in women
with increased risk of breast or other estrogen-dependent cancers).
Amenorrhoea
Amenorrhoea is the absence of menstrual periods
in a woman during her reproductive years.
• Primary amenorrhoea is defined as the absence of
menstrual periods by age 14 in a girl without
breast development or by age 16 in a girl with
breast development.
• Secondary amenorrhoea is defined as the absence
of menstrual periods for more than 3 months in a
woman who has previously had an established
menstrual cycle.
Aetiology of amenorrhoea
Considerable overlap exists between causes of primary
and secondary amenorrhoea. All causes of secondary
amenorrhoea can also present as primary amenorrhoea.
• Functional hypothalamic amenorrhoea
Stress, weight loss, excessive exercise, eating disorders
(anorexia nervosa, bulimia)
• Pituitary and hypothalamic tumours and
infiltrative lesions
Pituitary adenomas, craniopharyngiomas,
haemochromatosis
Aetiology of amenorrhoea
• Hyperprolactinaemia
Prolactinomas or tumours causing pituitary stalk
compression
• Congenital gonadotrophin - releasing hormone
deficiency
Kallmann’s syndrome, idiopathic
• Premature ovarian failure (Premature ovarian failure is
defined as primary hypogonadism (lack of folliculogenesis and
ovarian oestrogen production) before the age of 40 years.)
Chromosomal abnormalities (e.g. Turner’s syndrome),
autoimmune, iatrogenic (surgery, chemotherapy,
radiation), FMR1 gene premutation carriers,
galactosaemia
Aetiology of amenorrhoea
• Uterine and vaginal outflow tract disorders
Congenital anatomical abnormalities or acquired
(Asherman’s syndrome)
• Thyroid dysfunction
Hypothyroidism or thyrotoxicosis
• Hyperandrogenism
Congenital adrenal hyperplasia, polycystic ovary
syndrome
Investigations
• A pregnancy test
• ultrasound and/or magnetic resonance imaging (to demonstrate the
presence or absence of the uterus and vagina, and vaginal or cervical
outlet obstruction).
• Serum FSH levels are elevated in premature ovarian failure (due to
reduced inhibition by ovarian oestradiol and inhibin).
• A low or normal serum FSH suggests functional hypothalamic
amenorrhoea, congenital GnRH deficiency or other disorders of the
hypothalamic – pituitary axis.
• Serum prolactin levels (to exclude hyperprolactinaemia as a cause of
secondary hypogonadism)
• Serum thyroid - stimulating hormone (TSH) and free thyroxine
(T4)(hypothyroidism and thyrotoxicosis)
• Serum androgens (hyperandrogenism)
Treatment
• Functional hypothalamic amenorrhoea can be
reversed in most cases by weight gain, reduction in
exercise intensity or resolution of illness or stress.
• Pituitary tumours may require surgery.
• The majority of women with prolactinomas are
successfully treated with dopamine agonists.
• Patients with irreversible gonadotrophin deficiency
should receive oestrogen replacement therapy and
progesterone.
• In girls with primary amenorrhoea and delayed puberty,
oral ethinylestradiol is started at a low dose to promote
breast development and adult body habitus.
Polycystic ovary syndrome
(PCOS)
The Rotterdam criteria for the diagnosis of
polycystic ovary syndrome include two out of
the following three:
• Oligomenorrhoea/amenorrhoea
• Hyperandrogenism: clinical (acne, hirsutism,
male - pattern hair loss) and/or biochemical
(elevated serum androgen levels)
• Polycystic ovaries on USG
Aetiology
PCOS is frequently associated with obesity,
insulin resistance (impaired glucose intolerance,
diabetes) and dyslipidaemia.
Both environmental factors (e.g. related to diet
and the development of obesity) and a number of
different genetic variants may influence the
development of PCOS.
Clinical presentations of PCOS
• menstrual abnormalities
infrequent or absent menses (oligomenorrhoea or
amenorrhoea), infertility and occasionally
dysfunctional uterine bleeding resulting from
chronic anovulation
• hyperandrogenism
acne, hirsutism (excess hair growing in a male
distribution) and male-pattern hair loss
• obesity, impaired glucose intolerance/
diabetes mellitus and dyslipidaemia are frequently
seen in patients with PCOS.
Investigations
• Luteinizing hormone (usually raised)
• FSH (to rule out premature ovarian failure)
• Androgens: testosterone, androstenedione and
dehydroepiandrosterone sulphate (usually
raised)
Investigations
Exclude other causes of menstrual irregularity or
hyperandrogenism by performing the following tests:
• Hyperprolactinaemia: serum prolactin.
• Hypo/hyperthyroidism: free thyroxine and thyroid –
stimulating hormone.
• Congenital adrenal hyperplasia: 17 hydroxyprogesterone
• Cushing’s syndrome: free cortisol
• Androgen - secreting ovarian or adrenal tumours:
serum testosterone
Investigations
Ultrasound
The presence of 12 or more follicles in each
ovary measuring 2 – 9 mm, and/or an increased
ovarian volume of more than 10 mL, is part of
the Rotterdam criteria for the diagnosis of PCOS
Treatment
• Lifestyle changes (diet and exercise) and modest weight
loss may result in a restoration of ovulatory cycles and an
improvement in hyperandrogenism and insulin resistance.
Metformin is a reasonable adjunct to diet and exercise for
patients with PCOS who are obese.
• Oral contraceptive pills are the treatment of choice for
hirsutism or other androgenic symptoms.
Antiandrogens used in treatment of hirsutism include the
following:
• Flutamide
• Finasteride
• Cyproterone acetate
Dear students!
To prepare this topic properly you need to use
both undermentioned books :
References:
1. Lecture notes. Endocrinology and Diabetes:
Chapters 19-22, pages 116-142
2.Harrisons Endocrinology:
pages 201-204 (amenorrhea),
pages 216-221 (hirsutism and virilisation)
pages 146-149 (Turner syndrome, Klinefelter syndrome),
Questions:
1. Physiology of reproductive system hormones (males, females), they effects.
2. Amenorrhea: classification, aetiology, differential diagnosis, treatment.
3. PCOS: etiopathogenesis, clinical manifestations, diagnosis,differential diagnosis, treatment.
4. Male hypogonadism: etiopathogenesis, classification, clinical manifestations, diagnosis,
differential diagnosis, treatment
5.Gynaecomastia: etiopathogenesis, clinical manifestations, diagnosis, differential diagnosis,
treatment
6.Hirsutism and virilization: etiopathogenesis, clinical manifestations, diagnosis and differential
diagnosis, treatment options.
7.Disorders of sex development (Turner syndrome, Klinefelter syndrome)-clinical manifestation,
diagnosis and differential diagnosis, treatment options.