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Editor-in-Chief
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Consultant in Fetal and Maternal Medicine, Department of Obstetrics and Gynaecology,
Queens Medical Centre, Nottingham, UK
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Professor of Obstetrics and Gynaecology,
Department of Obstetrics and Gynaecology,
St. Georges Hospital Medical School, London, UK
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Catherine Aiken MB/BChir MA PhD MRCP MRCOG
Specialist Registrar (ST5) and Academic Clinical Lecturer in Obstetrics and Gynaecology,
Addenbrookes Hospital, Cambridge, UK
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CASE-BASED LEARNING
Adolescent gynaecology
Mohamed Otify
Tahir Mahmood
Abstract
Paediatric and adolescent gynaecology involves the care of young
women and their special needs as their bodies change and grow
into adulthood. Diagnosis and management of common problems in
gynaecology in this age group requires knowledge regarding congenital reproductive anomalies, disorders of gender development, reproductive endocrinopathies, gender identity, and gynaecologic
malignancies. Gynaecologic disease states in paediatric patients
frequently present with vulval and vaginal manifestations, while
those in the adolescent age range present as abdominal-pelvic pain
and abnormal menstrual bleeding. A case-based learning of common
childhood gynaecologic disorders and their treatment is presented.
Introduction
Paediatric and adolescent gynaecology requires knowledge of
normal female embryological development, endocrine function
around adolescent years, fertility, the impact of female genital
system abnormalities on gender identity and mental health, and
the medical and surgical management of these systems. Best care
is administered with a multidisciplinary team (including
adolescent gynaecologists, paediatricians, paediatric surgeons,
endocrinologist, clinical geneticists and psychologists) to treat
the underlying disorder, preserve fertility and future sexual
function, and maintain a healthy mental state. This review presents different scenarios in children presenting with a diverse
range of gynaecological diseases requiring knowledge of these
systems.
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CASE-BASED LEARNING
Clinical ndings
Relevant history includes age at menarche, breast bud development, and appearance of pubic hair, duration of periods, amount
of menstrual flow, presence of pain or cramping, time between
periods, diet, and exercise patterns. Girls with PCOS most
frequently have regular periods to start and then develop irregular periods. Growth charts of adolescents with PCOS can
demonstrate a marked increase in weight following initiation of
menses. A family history for PCOS and diabetes is also obtained.
Adolescents with PCOS and hyperandrogenism can demonstrate Hirsuitism and virilisation. Hirsuitism is characterized by
excess facial and body hair. The frequency of Hirsuitism is
directly related to age, with adolescents being least commonly
affected. Signs of virilisation include deep voice, frontal and
temporal balding, increased muscle bulk, decreased breast size,
and clitoral hypertrophy. The clinical finding of acne is generally
normal during adolescence and can be confusing in virilised
adolescents. Acanthosis nigricans, characterized by darkening of
the skin on the back of the neck and other areas, is associated
with moderate to severe insulin resistance.
At first clinic appointment, patient height, weight, BMI, waist
circumference, and blood pressure are evaluated. Affected adolescents generally have a central obesity pattern.
Treatment
Girls with PCOS require family and personal counselling to better
understand the long-term impact of this diagnosis. Depression
and anxiety can develop as the patient experiences the clinical
impact of their disease. The treatment of PCOS is symptomatic.
General recommendations include, diet, exercise, and weight
reduction, which can improve serum androgen, insulin, LH and
lipid abnormalities. Further treatment may be needed if the
adolescent woman with treated PCOS desires pregnancy.
Medroxyprogesterone or Norethisterone administered for 10
e14 days each month can be used to avoid abnormal endometrial proliferation and facilitate normal ovarian androgen production in adolescents. The low-dose oral contraceptives pills
can also be used in girls with regular menses. Such treatment will
provide contraception, prevent endometrial hyperplasia,
decrease testosterone levels, and can improve hirsuitism and
acne. Adolescents with irregular menstrual cycles may also be
started on oral contraceptives without evaluation for PCOS. Girls
already taking oral contraceptives can be withdrawn for 3
months if biochemical testing is needed to diagnose hyperandrogenism or PCOS. Other contraceptive measures e.g. barrier
contraception should be planned for during this testing period,
when appropriate.
The use of metformin has been beneficial in increasing insulin
sensitivity and decreasing serum LH and free testosterone levels.
The use of metformin has been associated with the return of
normal menstrual cycles in 68e95% of girls with prior normal
cycles.
Antiandrogens such as spironolactone, flutamide, or cyproterone can be combined with oral contraceptive pills to decrease
testosterone levels and treat hirsutism. GnRH analogues are
generally reserved for girls that do not respond to these treatments or do not tolerate oral contraceptive pills. Long-term use of
GnRH analogy can lead to bone demineralization, hot flushes,
and atrophic vaginitis due to chronic low oestrogen levels, and
may require monitoring as long as they are on this treatment.
Laboratory testing
Patients are diagnosed with PCOS after excluding the diagnosis of
congenital adrenal hyperplasia, androgen-secreting tumours,
high-dose exogenous androgens, and Cushings syndrome. A
basal morning 17-hydroxyprogesterone level is determined in
order to exclude 21-hydroxylase deficient non-classic adrenal
hyperplasia in hyperandrogenic patients.
Serum follicle stimulating hormone (FSH) and 17b-oestradiol
levels are determined to exclude hypogonadotropic hypogonadism in young women presenting with oligo- or anovulation.
The free androgen index (total testosterone level divided by
sex hormone-binding globulin level) and serum dehydroepiandrosteronesulphate (DHEAS) levels are used to identify
biochemical hyperandrogenism. A dexamethasone suppression
test is performed to exclude Cushings syndrome.
At subsequent review appointments, consideration should be
given to assess fasting serum glucose level, total, and low-density
lipoprotein and high-density lipoprotein cholesterol levels to
determine insulin resistance. Oral glucose tolerance testing is
performed as indicated.
Luteinizing Hormone (LH) levels are significantly elevated in
about 60% of girls with PCOS, due to the increased amplitude
and frequency of LH pulses. The LH/FSH ratio is elevated in
about 95% of affected patients. The clinical relevance of LH in
PCOS and the potential effects of LH suppression with gonadotropin releasing hormone (GnRH) analogues are not known, so
LH levels are not routinely determined.
Thyroid hormones are known to alter androgen metabolism
and contribute to hyperandrogenism. However, the incidence of
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CASE-BASED LEARNING
ultrasound. Post-pubertal adolescents develop cysts after a failure of ovulation or with the persistence of ovarian follicles.
About one in 1000 symptomatic ovarian cysts in premenopausal females are malignant, increasing to about three in 1000
at age 50. The incidence of adnexal masses in girls less than 18
years of age has been estimated as 2.6 per 100,000. Ten percent
of ovarian masses have been reported to be non-ovarian in
origin. Benign mature teratomas (dermoid cysts) are the most
common benign tumour in girls less than 20 years of age. About
10% of ovarian masses in this age group are malignant. Malignant immature teratomas comprise less than 1% of ovarian teratomas and 10e20% of malignant tumours in this age range.
Malignant immature teratomas comprise about 10% of germ
cell tumours. Germ cell tumours can be associated with elevations in serum a-fetoprotein (a-FP) and b-human chorionic
gonadotropin (b-hCG) levels. Elevated serum a-FP levels have
been reported in 33e65% of patients with malignant immature
teratoma. About 26% of affected patients also have associated
ipsilateral mature cystic teratoma and 10% contralateral immature teratoma. Malignant immature teratomas are diagnosed
most frequently between the ages of 10 and 20 years, with a
median age of 17 years.
Treatment
Patients are treated according to tumour stage. Clinical staging
for malignant immature teratoma is:
Stage 1: tumour confined to the ovary
Stage 2: local tumour extension to the fallopian tubes,
uterus, or other pelvic organs
Stage 3: tumour spread confined to the peritoneum or
abdominal lymph nodes
Stage 4: tumour spread outside the peritoneal cavity
Simple ovarian cysts less than 50 mm in diameter are usually
functional and resolve over two to three menstrual cycles without
intervention. Simple ovarian cysts 50e70 mm in diameter are
followed with yearly ultrasound to identify any change. Larger
simple cysts are usually evaluated by using MRI or laparoscopic
surgery. The use of oral contraceptives has not been helpful in
treating functional ovarian cysts. Oral contraceptives have been
useful in post-pubertal females for the prevention of ovarian cysts.
Ovarian cysts that persist or increase in size during follow-up
are usually not functional cysts and are managed surgically.
Mini-laparotomy may be used to resect very large cysts or solid
tumours. Adolescents and their parents should be counselled
regarding the possibility of ovarian loss with surgery.
Malignant immature teratomas are usually unilateral and are
diagnosed with laparoscopic oophorectomy of the affected
gonad. Patients with stage 1 malignant immature teratomas are
treated with oophorectomy and observation. Ovary sparing surgery is performed when possible in order to better preserve
fertility. Visual inspection of the abdominal contents is performed during surgery to identify malignant spread. Pelvic
washings, inspection of the contralateral ovary, and intraoperative frozen section are also performed. Patients with large
tumours are converted to open surgery to better prevent tumour
spillage and to ease removal. The benefit of lymphadenectomy in
women with lymphadenopathy is not clear.
Patients with stage 2, 3, and 4 malignant immature teratomas
are treated with ovarian surgery plus chemotherapy using bleomycin, etoposide and cisplatin (BEP). Limiting chemotherapy
related toxicities include pulmonary toxicity with bleomycin,
decreases in glomerular filtration rate and high tone hearing loss
with cumulative doses of platinum exceeding 300e400 mg/m2,
and the late development of myeloid malignancies with
etoposide. The rarity of these tumours has slowed the evaluation
of chemotherapy in randomized controlled clinical trials.
Fertility after conservative surgery and chemotherapy is found
in 70e83.3% of adolescents treated with conservative surgery
Clinical ndings
Adolescents with ovarian masses can present with abdominal
pain, nausea, vomiting, a palpable abdominal mass, increasing
abdominal girth, or precocious puberty. Larger ovarian tumours
are predisposed to torsion, which typically present with a sudden
onset of severe abdominal pain, fever, nausea, vomiting, and
leucocytosis.
A thorough history and physical exam are performed to
evaluate genitourinary and gastrointestinal symptoms. Physical
exam should take special care to identify lymphadenopathy,
abdominal tenderness, and the presence of ascites. Menstrual
cycle, sexual, and contraceptive history are obtained. Any relationship of symptoms to menstrual cycle is determined. Family
history for ovarian or breast cancer is obtained. Symptoms suggestive of ovarian malignancy are identified, including history of
persistent abdominal distension, change in appetite, pelvic or
abdominal pain, increased urinary urgency and/or frequency,
and weight loss.
Laboratory testing
Pelvic ultrasound is performed to identify and characterize
ovarian tumours and cysts. Sensitivity of pelvic ultrasound has
been reported as 95%, specificity as 91%, positive likelihood
ratio as 10.4 and negative likelihood ratio as 0.06.
Chest and abdominal imaging with CT or magnetic resonance
(MRI) are useful in further staging adolescents with complex or
solid ovarian tumours. Malignant immature teratoma usually
present as a large, heterogeneous mass with a prominent solid
component on imaging studies. Calcifications and small foci of
fat are often present. The presence of these three findings in an
adolescent is suggestive of malignant immature teratoma. Haemorrhage is occasionally seen. Identification of a solid portion
with numerous cystic areas is helpful in distinguishing malignant
immature teratoma from benign mature cystic teratoma. Benign
mature teratomas are usually smaller and contain more cystic
areas than malignant immature teratoma.
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CASE-BASED LEARNING
and chemotherapy, and no fetal abnormalities have been reported. Radiation therapy is avoided in order to preserve fertility,
unless there is residual tumour after second-line chemotherapy
and surgery.
The long-term recurrence rate after surgical excision of
mature cystic teratomas is around 4%. A patient with young age
(<30 years old) or large cyst (8 cm in diameter) or bilateral
cysts is at high risk of recurrence, which is even higher when a
patient has more than one of these factors.
In cases of immature teratomas recurrence was reported in
18% of the patients with grade 1 disease, in 37% of the patients
with grade 2 disease, and in 70% of the patients with grade 3
diseases.
Laboratory testing
Standard testing includes a pregnancy test, and determination of
serum FSH, LH, prolactin, total testosterone, sex hormonebinding globulin and thyroid stimulating hormone levels. A
pelvic ultrasound can be useful in defining gonadal and uterine
anatomy.
Elevated serum FSH levels are associated with ovarian dysgenesis, leading to examination of the patients karyotype. A 46 XY
karyotype is associated with a high risk for gonadoblastoma or
dysgerminoma arising from retained testes. A normal serum FSH
level with no visualization of the uterus on ultrasound is compatible
with Mullerian agenesis or androgen insensitivity syndrome. Serum
testosterone levels are in the normal range in women with Mullerian agenesis and in the normal range for genotypic men (phenotypic women) with androgen insensitivity. A normal serum FSH
level with breast development and ultrasound visualization of
blood in the uterus (hematometra) or vagina (hematocolpos) is
compatible with an obstructed outflow tract. A low or normal
serum FSH level with a normal uterus visualized on ultrasound is
compatible with constitutional delay of puberty or congenital GnRH
deficiency. Magnetic resonance imaging (MRI) is the mainstay in
the imaging evaluation of Mullerian agenesis.
Treatment
Treatment is dependent on the nature of the underlying disorder.
Medical treatment is indicated for thyroid disease. Drugs that
cause prolactin secretion are identified, and modified as
indicated.
Patients with Turners syndrome and testicular feminization
have particular health risks and should be referred for specialist
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CASE-BASED LEARNING
syndrome, and hypophosphatemic rickets. Patients are recognized clinically by the triad of peripheral precocious puberty,
irregular cafe-au-lait spots, and fibrous bone dysplasia. Girls with
MAS have recurrent follicular cysts and cyclic menses.
Amenorrhoea can be caused by obstructions in menstrual
outflow. The most common cause of outflow obstruction is an
imperforate hymen. The hymenal membrane separates the
vaginal lumen from the urogenital sinus and usually ruptures
before birth, leaving a thin fold of membrane. New born children
with imperforate hymen have stimulation of vaginal secretions
from maternal oestradiol and a bulging introitus on physical examination due to mucocolpos. The mucous is resorbed as oestradiol levels drop and this finding is not subsequently observed
again until menstruation, when it can present as hematocolpos.
Clinical ndings
Children with precocious puberty have accelerated linear growth
for age, advanced bone age, and pubertal levels of serum LH and
FSH. Untreated precocious puberty can result in accelerated
skeletal development and shorter adult height. Physical examination includes evaluation of height, weight, and height velocity
(cm/year), assessment of visual fields, and examination for cafeau-lait spots. Vulvar or vaginal inspection reveals a tense, shiny,
bulging membrane. Secondary sexual maturation is evaluated
using the Tanner stage.
Some children develop central precocious puberty secondary to
CNS pathology, a condition called neurogenic CPP. Lesions causing
neurogenic CPP include hamartomas of the tuber cinereum, astrocytomas, ependymomas, pinealomas, optic and hypothalamic gliomas, hydrocephalus, cysts, trauma, CNS, inflammatory disease,
and congenital midline defects, such as optic nerve hypoplasia.
Children with neurofibromatosis can develop neurogenic CPP with
the occurrence of optic gliomas. Children with CPP should undergo
brain contrast-enhanced MR imaging to exclude such lesions.
Children receiving CNS irradiation can develop precocious puberty
secondary to loss of growth hormone secretion.
The most common cause of PPP in girls is a large functional
ovarian follicular cyst. Affected patients exhibit early breast
development followed by vaginal bleeding due to oestrogen
withdrawal when the cyst regresses. Functional cysts can appear
and regress spontaneously, leading to a conservative management plan. Large cysts have a higher risk of ovarian torsion.
The adolescent girl with an imperforate hymen will present
after menarche with cyclic abdominal or pelvic pain and hematocolpos, a perirectal mass from sequestration of blood in the
vagina, and primary amenorrhoea. Physical exam reveals a
bulging hymenal membrane with a bluish discolouration due to
retained blood. Marked distension of the vagina can lead to back
pain, pain with defecation, and problems with urination.
Transverse vaginal septae can present in a similar fashion.
Laboratory testing
Routine testing includes bone age assessment, LHRH stimulation
testing, and determination of serum FSHF, LH, testosterone, and
oestrogen levels. Pelvic ultrasound is used to assess ovarian and
uterine anatomy. Patients with normal variations in the onset of
puberty can have mildly elevated levels of serum DHEAS for age.
Patients with normal variations in the onset of puberty are closely
followed to identify their complete progression into puberty.
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CASE-BASED LEARNING
Conclusion
The initiation and normal progression of puberty in adolescents
can be affected by numerous diseases and present in varied
ways. The cases presented, PCOS, primary amenorrhoea, and
precocious puberty, well characterize the diversity in findings in
the endocrine systems, clinical history, and physical examination. Characterization of embryologic development, pubertal
development, and associated endocrine abnormalities is performed for each disease state. The lack of age normal standards
for ovarian and uterine development can add to the complexity of
this evaluation. Identification of abnormal findings, such as
virilisation, can be important in making a rapid correct initial
diagnosis. Multidisciplinary input is vital to counselling process
with a team consisting of paediatric endocrinologist, gynaecologist with interest in pre-and adolescent gynaecology, paediatric
surgeon and psychiatrist.
A
FURTHER READING
Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic
ovarian syndrome: the Rotterdam criteria are premature. J Clin
Endocrinol Metab 2006; 91: 781e5.
ger J. Precocious puberty. N Engl J Med 2008; 358:
Carel JC, Le
2366e77.
Devaja OM, Papadopoulos AJ. Current management of immature
teratoma of the ovary. Arch Oncol 2000; 8: 127e30. 6.
Kent SC, Legro RS. Polycystic ovary syndrome in adolescents. Adolesc Med 2002; 13: 73e88.
Ledger WL, Atkin SL, Sathyapalan T. Long-term consequences of polycystic ovary syndrome. Green-top Guideline No. 33 2014; 1e15.
Zolton JR, Maseelall PB. Evaluation of ovarian cysts in adolescents.
Open J Obstet Gynecol 2013; 3: 12e6.
Treatment
Untreated women achieve a mature height of 151 cme155 cm.
Treatment with GnRH agonists is effective in improving adult
height of children diagnosed before 6 years of age. The benefit of
treating girls diagnosed at ages 6e8 years is not clear. Girls in this
age range with advanced bone age or a height below the 25th
percentile with predicted heights less than 150 cm or who are well
below their target height are considered for treatment. No benefit
has been found in treating children presenting at ages greater than
8 years. Best results are achieved in girls without advanced bone
maturation. Treatment should be stopped once an acceptable age
of puberty is reached. Normal gonadotropin secretion recommences about 3e4 months after cessation of treatment, with
normal pubertal development and fertility. Children with precocious puberty due to radiation and growth hormone deficiency
require additional growth hormone supplementation.
The profound physical and hormonal changes associated with
precocious puberty can lead to difficulties in interpersonal relationships, disruptive behaviour, and an early onset of sexual
behaviour. Counselling for the patient and family are indicated.
Treatment outcomes are monitored using age and gender
appropriate growth charts, growth velocity, bone age, pubertal
progression, Tanner staging, and determination of serum gonadotropins and sex steroid levels.
Practice points
C
C
C
221
Polycystic ovarian syndrome is often undiagnosed as many adolescents do not have regular menstrual cycles. Symptomatic
treatment of these young women with oral contraceptive pills can
contribute to missing this diagnosis.
The four most common causes of amenorrhoea are polycystic
ovarian syndrome, hypothalamic amenorrhoea, ovarian failure,
and hyperprolactinaemia.
90% of central precocious puberty in girls is constitutional.
Many adolescents with gynaecologic pathology present with
complex problems that are best managed with a team approach.
REVIEW
Endometrial cancer
Wendy MacNab
Mohamed K Mehasseb
Abstract
Endometrial cancer is the most common gynaecological malignancy,
and an understanding of its presentation and management options
is required for all gynaecologists. The surgical management of endometrial cancer has expanded to include laparoscopic surgery, and
debate is ongoing regarding the merits of pelvic and para-aortic lymphadenectomy. Our understanding of the biology of endometrial cancer may help determine which women may benet most from chemoor hormonal therapy in an adjuvant setting. Pelvic radiation is associated with improved local control. Combination therapy with radiation
and chemotherapy is under evaluation. The use of sentinel lymph
node sampling is an area for further research and development.
Introduction
Worldwide, endometrial carcinoma is only second to cervical
cancer in frequency among female genital tract cancers. In the
Western world, it is the commonest female genital tract malignancy, accounting for nearly 50% of all new gynaecologic cancers.
Its incidence is rising due to increased life expectancy, obesity
epidemic, and the fewer hysterectomies performed for benign
diseases. Most cases (95%) occur in women over 40 years of age,
mostly in the sixth and seventh decades of life (75e85%). The
overall lifetime risk of developing endometrial carcinoma is 2.5%.
Endometrial carcinoma is usually confined to the uterus at the time
of diagnosis and as such, carries an excellent prognosis with high
curability. However, women with high-risk factors (25%)
including increased age, co-morbidities, higher tumour grade,
aggressive histology, and advanced stage represent real challenges.
Risk factors
i. Obesity
Obesity accounts for about 40%e50% of endometrial cancer
cases in the developed world. Endometrial carcinoma was the
first malignancy to be recognized as being linked to obesity. A
linear increase in the risk of type 1 endometrial cancer with
increasing weight and BMI has been observed (Table 1). Overweight and obese women have two to four times greater risk of
developing endometrial cancer than do women of a healthy
weight, regardless of their menopausal status. Obesity affects the
production of peptides (e.g. insulin and IGF-1, SHBG) and steroid
hormones (i.e. oestrogen, progesterone, and androgens). It is
likely that prolonged exposure to high levels of oestrogen and
insulin associated with obesity may contribute to the development of endometrial cancer.
Obesity in the menopause produces a state of excess oestrogen
production. This is due to the peripheral conversion of androgens
produced by the adrenal glands and ovaries into oestrone, by the
enzyme aromatase, in the adipose tissue. Prolonged unopposed
oestrogen exposure will lead to a continuous spectrum of endometrial changes from proliferative endometrium through hyperplasia/polyps to carcinoma (Figures 1 and 2). Avoiding weight
gain lowers the risk of endometrial and postmenopausal breast
Pathology
Histologically and biologically, endometrial cancer is broadly
classified into two main categories: type 1 and type 2. The vast
majority (80%) of endometrial malignancies are type 1 i.e. endometrioid adenocarcinoma, arising from the glandular epithelium,
usually on a background of atypical hyperplasia. Endometrial
adenocarcinoma is found in up to 50% of cases of complex atypical hyperplasia. Endometrioid tumours are assigned a grade (1
e3) depending on the degree of differentiation and nuclear
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REVIEW
Incidence
Mortality
25e27.4
27.5e29.5
>30
21%
9%
43%
21%
273%
228%
289%
246%
Diagnosis
Endometrial cancer most commonly presents as postmenopausal bleeding (PMB) (90%), although only 10% of
women with PMB will have cancer. Other women can present
with persistent postmenopausal vaginal discharge due to pyometra. Premenopausal women usually present with significant
worsening in menstrual pattern, or with incidental finding of
abnormal endometrial cells on routine cervical cytology. Malignant endometrial cells appear on cervical cytology screening
smears in 25e50% of women with endometrial cancer. The
significance of normal endometrial cells in cervical smears in
postmenopausal women is less clear. Presentation as a result of
metastatic disease is uncommon and pain is generally not a
feature.
Prompt referral and initial assessment should take place in
rapid-access clinics, identifying risk factors and comorbidities. A pelvic examination should be conducted to
exclude obvious lower genital tracts cancers. A transvaginal
ultrasound scan is recommended to measure the endometrial
thickness and identify any ovarian mass. A thin endometrium
(<5 mm) in the postmenopausal woman has a high negative
predictive value for endometrial cancer and is reassuring. Ultrasound is less helpful in women taking tamoxifen because
typical morphological changes seen with tamoxifen use often
result in false positive ultrasound findings. Hysteroscopy and
endometrial sampling can be performed safely in the outpatient setting in >80% of women, providing prompt reassurance and a diagnosis in those cases where an endometrial
abnormality is suggested on ultrasound scan. The pipelle is the
best endometrial sampling device, with detection rates for
endometrial cancer in postmenopausal and premenopausal
women of 99.6% and 91%, respectively. The sensitivity for
the detection of endometrial hyperplasia is 81%, with a
specificity of 98%.
Table 1
Investigations
Once a diagnosis of endometrial cancer has been made, discussion at a recognized specialist gynaecological cancer MDT should
take place. A blood count, renal biochemistry and liver function
tests are performed and further imaging is undertaken to identify
metastatic disease and aid treatment decisions. A chest X-ray is
done as a minimum to identify lung metastases. In some cases
where the risk of lung metastases is higher e.g. carcinosarcoma,
computed tomography scanning (CT) of the thorax may be used
instead. CT may also be helpful in assessing suspected upper
abdominal metastatic disease. Magnetic resonance imaging
(MRI) is used to assess the depth of myometrial invasion and to
identify extension into cervical stroma. MRI is sensitive for this
purpose, accurately predicting depth of invasion and cervical
extension in 92% of cases.
Screening
Although many endometrial cancers develop by way of a precursor lesion (i.e. atypical endometrial hyperplasia), routine
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REVIEW
cytologic evaluation, total extra-fascial hysterectomy with bilateral salpingo-oophorectomy, and appropriate surgical staging in
women considered at risk for extra-uterine disease. Many would
now consider laparoscopic hysterectomy, including total laparoscopic hysterectomy (TLH) and laparoscopically assisted
vaginal hysterectomy (LAVH) to be standard practice, although
careful patient selection is required. Post-operatively, many
women will require some type of adjuvant therapy to help prevent vaginal vault recurrence and to address disease in lymph
nodes.
Surgical considerations
The obese patient
An elevated BMI increases the risk of perioperative complications and mortality, particularly in the presence of comorbidities such as diabetes, hypertension, coronary artery
disease, sleep apnoea and joint problems. The risks are further
increased with morbid obesity (BMI >40). Obese women
should receive careful counselling about the increased risk of
complications and technical difficulties that may be encountered during surgery. They also require a thorough preoperative
evaluation including cardiovascular and respiratory assessment. Assistance with proper dosing and monitoring of medications should be considered. During surgery, control of the
airway is critical in obese patients and can be even more
difficult in laparoscopic surgery. Venous access can be problematic. Manual handling of obese women can be challenging,
and special hospital beds and operating tables should be
available, to help reduce the risks to staff and patient. Obese
women are at a much higher risk for postoperative complications compounded by associated co-morbidities. Thus, respiratory or cardiac failure, venous thromboembolism, aspiration,
wound infection and dehiscence are all more common in obese
women. Planned admission to high-dependency units, to optimize the physiological reserves, is often advisable. In obese
patients laparoscopic hysterectomy is optimal as it results in
reduced post-operative complications and a shorter hospital
stay compared to open/abdominal surgery.
The abdominal wall anatomy is often distorted by the overhanging skin and fat (panniculus). Obesity is recognized as a
potential limiting factor in the application of laparoscopic surgery
because of a higher rate of failed entry, hindered manipulation
and poor views. Obesity may not allow steep Trendelenburg
because of unacceptably high peak inspiratory pressure. In
addition, obesity may prevent adequate mobilization of the small
bowel out of the pelvis to allow for proper pelvic visualization.
Nevertheless, laparoscopic surgery has additional benefits for the
obese: they have less postoperative ileus, fewer wound infections
and they mobilize more quickly than those undergoing laparotomy. Obesity presents problems with laparotomy incision
placement and closure. Adequate wound antisepsis is necessary,
as obese women are at increased risk of wound infection and
wound failure. Possible aetiologies include decreased oxygen
tension, immune impairment, and tension or secondary
ischaemia along suture lines. Access to the pelvis can be challenging and there is a higher incidence of intraoperative complications due to problems with access or distorted anatomy.
Difficulty with haemostasis, particularly when removing the
Figure 2 A surgical specimen following a total abdominal hysterectomy and bilateral salpingo-oophorectomy performed for the treatment of high-grade endometrial carcinoma. Note the presence of a
bulky enlarged uterus with endometrial cancer lling and distending
both cornua and the right fallopian tube.
Staging
The staging system used for endometrial carcinoma is the International Federation of Gynaecology and Obstetrics (FIGO)
classification, revised in 2009. The staging is based upon findings
at surgery and histological assessment of the surgical specimen,
and provides prognostic information (Tables 2 and 3).
After omission from the 2009 FIGO staging for endometrial
carcinoma, the need for peritoneal cytology and the significance of a
positive result became controversial. In women with stage I and II
disease, positive peritoneal cytology results do not influence survival. Poor prognosis associated with positive washings is most
common in women with other adverse prognostic factors: i.e. grade
3 histologic types, metastases to the adnexa, deep myometrial invasion, or positive pelvic or para-aortic nodes. Positive peritoneal
cytology may thus carry a prognostic significance only when the
endometrial carcinoma has spread beyond the uterus.
Management
The standard treatment for endometrial carcinoma remains surgical and comprises of collection of peritoneal fluid washings for
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Chemotherapy
The value of adjuvant systemic chemotherapy in women with
high-risk early stage endometrial cancer is still controversial.
PORTEC-3 study is a phase III randomized trial comparing chemoradiation and adjuvant chemotherapy (four cycles of carboplatin and paclitaxel) versus pelvic radiation alone in high-risk
and advanced stage disease. This study should determine
whether radiotherapy or chemotherapy improves overall survival and failure-free survival. Two additional GOG studies are
examining the role of adjuvant chemotherapy in the treatment of
endometrial carcinoma (GOG 249 and GOG 258).
Stage II
Stage III
IIIA
IIIB
IIIC
IIIC1
IIIC2
Stage IV
IVA
IVB
Table 2
1
2
3
Table 3
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Extent of lymphadenectomy
When full surgical staging is performed, a bilateral pelvic and
para-aortic lymphadenectomy is increasingly advocated
because positive lymph nodes (including isolated para-aortic
lymph nodes) can occur in all grades. The clinico-pathologic
factor most strongly related to para-aortic nodal metastasis is
pelvic lymph node metastasis, hence, systemic para-aortic
lymphadenectomy is advocated on all high-risk women, or in
women with two or more positive pelvic lymph nodes. However, this is a major surgery to undertake in women who are
usually elderly and obese, with other co-morbidities. An
extensive para-aortic lymphadenectomy significantly increases
operating time and blood loss and also increases postoperative
morbidity, particularly lower limb lymphoedema (in about 20%
of women). It could thus be argued that primary prevention of
lymphoedema by selective use of pelvic lymphadenectomy and
avoidance of systematic para-aortic lymphadenectomy is highly
desirable.
Therapeutic role of lymphadenectomy
The therapeutic role of lymphadenectomy is less well defined.
The current available evidence from the ASTEC trial does not
support the claim that lymphadenectomy in endometrial cancer
is therapeutic. Unfortunately, there are several reasons why the
ASTEC trial could have failed to show improved overall survival with routine lymphadenectomy. The trial required only a
pelvic lymphadenectomy and utilized a second randomization
for pelvic radiation for disease characteristics, which, following
a negative nodal dissection, is typically avoided. Likewise,
vaginal vault radiation was permitted as per institutional
practice irrespective of the assignment to pelvic radiation or
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Future directions
Advances in the understanding of the molecular basis of endometrial cancer may enable future development of more targeted
therapies.
PTEN is a regulatory protein, expressed most highly in oestrogen rich environments, and is involved in the regulation of
cellular growth, proliferation, survival and protein transcription. Mutations within PTEN are observed in many type 1
endometrial cancers, resulting in hyperactivation of mTOR
(mammalian target of rapamycin) and thus, inhibition of mTOR
and/or PI3K has been proposed as a potential treatment target.
As such mTOR inhibitors have been developed and demonstrated promising early results. Temsirolimus showed a 26%
response rate and 63% disease stabilization rate in a phase II
trial of chemotherapy nave women. These initial results have
prompted further trials in combination with established treatment regimens.
Inhibition of angiogenesis has also been proposed as a
mechanism for more targeted therapies. Correlations between
the expression of vascular endothelial growth factor (VEGF) and
prognostic factors in endometrial cancer have been observed.
Bevacizumab is a recombinant monoclonal antibody directed
against VEGF and several phase II trials are currently examining
its efficacy.
Epidermal growth factor (EGFR) is involved in the promotion
of cell proliferation and its overexpression has been implicated in
the development of a number of tumours. EGFR inhibitors have
had excellent effect in the management of both breast and colon
cancer. Whilst EGFR overexpression has been demonstrated in
both type 1 and type 2 endometrial cancers, the results of EGFR
inhibitor trials have been disappointing.
A
FURTHER READING
ASTEC Study Group. Efcacy of systematic pelvic lymphadenectomy
in endometrial cancer (MRC ASTEC trial): a randomised study.
Lancet 2009; 373: 125e36.
Ballester M, Dubernard G, Lecuru F, et al. Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial
cancer: a prospective multicentre study (SENTI-ENDO). Lancet
Oncol 2011; 12: 469e76.
Colombo N, Creutzberg C, Amant F, et al. on behalf of the
ESMO_ESGO_ESTRO Endometrial Consensus Conference
Working Group. ESMO-ESGO-ESTRO consensus conference
on endometrial cancer: diagnosis, treatment and follow-up. Ann
Oncol 2015; 1e26. http://dx.doi.org/10.1093/annonc/mdv484.
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Practice points
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In vitro fertilization
Indications
Since the birth of Louise Brown in 1978, a significant number of
developments in both clinical medicine and basic sciences have
given a chance to an increasing number of infertile couples to
have a baby. IVF was initially developed for women with tubal
disease, but its indications have now expanded significantly with
the changing socio-economic dynamics of our society. One
million babies were born in the first 25 years of IVF between
1978 and 2003 and it has been estimated that five million more
children have been born by the end of 2013. In the United
Kingdom (UK) 224,196 babies were born after IVF treatment
between 1991 and 2011. Table 1 provides a list of currently
accepted indications for ART.
Couples attending for their initial consultation before
embarking on IVF treatment should be given lifestyle advice
(Figure 1), offered general screening and specific infertility
investigation work-up.
Mythili Ramalingam
Punukollu Durgadevi
Tahir Mahmood
Abstract
In vitro fertilization, popularly referred to as IVF, changed the infertility
practice worldwide since its introduction in 1978 and it has continued
to evolve. Assisted reproductive technology (ART) refers to all treatments or procedures that include the in vitro handling of both
human oocytes and sperm, or embryos, for the purpose of establishing a pregnancy. Today ART is available globally, and the current practice is largely different from that which was used during the early days
of its inception. Although advances in laboratory technology and clinical practice have allowed IVF to evolve, it still remains invasive,
expensive and is associated with risks. This article reviews the current
indications for assisted reproduction and the preparatory steps before
starting treatment. It also summarizes the treatment cycle including its
main clinical and laboratory aspects, and the complications associated with treatment.
Introduction
It is estimated that infertility affects 1 in 7 heterosexual couples in
the UK. An increasing number of couples are seeking ART to
conceive and ultimately giving birth to a healthy live baby. ART
has opened many avenues for the infertile couples, albeit with a
financial and inherent psychological cost. The Warnock Report
(1984) set out the principles to safeguard the developments in
medicine and science related to human fertilization and embryology. This was followed by the creation of Human Fertilisation
and Embryology Act of 1990, and the establishment of a regulatory body The Human Fertilisation and Embryology Authority
(HFEA) in the United Kingdom.
IVF involves several steps: initial assessment and counselling,
suppressing the natural cycle, ovarian stimulation and monitoring, oocyte retrieval, fertilization of the eggs, embryo transfer
and luteal support, pregnancy test and confirmation of viability
of pregnancy with ultrasound.
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Pre-treatment interventions
Stress can have impact on the outcome of IVF treatment. It is
therefore important for couples to have access to professional
counsellors before, during and more importantly following failed
treatment. It is debatable if hysteroscopy or hysterosonography
should be done routinely before the start of IVF treatment in
order to improve sensitivity of detection of intrauterine adhesions or polyps that may escape detection by routine pelvic ultrasound. A recent Cochrane review has reported that
hysteroscopic removal of asymptomatic uterine polyp and
hydrosalpinges prior to IVF treatment improves pregnancy rates
significantly. The different types of IVF are summarized in Table
2.
Treatment cycle
The treatment cycle comprises of seven main steps as follows:
1. Pituitary down regulation
2. Ovarian stimulation
3. Monitoring of response to ovarian stimulation
4. Ovulation trigger
5. Oocyte collection
6. Luteal support
7. Embryo transfer
Pituitary down regulation (suppression)
During a natural cycle, there is a natural surge of LH in the midluteal phase before ovulation. The main aim of pituitary down
regulation is to avoid the effect of the intrinsic hormones on the
ovaries during the stimulation process. In addition to avoiding
the premature LH surge it also helps for planned oocyte retrieval
at a time that is convenient for the couples and staff in assisted
conception unit. The GnRH antagonist protocol reduces risk of
ovarian hyper-stimulation by allowing use of GnRHa trigger for
final oocyte maturation instead of Human Chorionic Gonadotropin (HCG). In women with oligo- or amenorrhoea progesterone withdrawal bleed is induced prior to down-regulation.
The most commonly used protocols for pituitary suppression
include long and short protocols (Figure 3). In these protocols
Gonadotropin releasing Hormone agonists (GnRHa) are used for
pituitary suppression. In the long protocol there is an initial
stimulatory effect of GnRHa on the pituitary leading to transient
surge of FSH and LH. This is usually followed by profound pituitary suppression 10e14 days later, leading to hypooestrogenic state amounting to menopausal status. Pituitary
suppression is confirmed by transvaginal measurement of
Table 1
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Lifestyle advice
Lifestyle advice
Smoking cessation
Weight
Stopping alcohol/
recreational drugs
Folic acid
Reduces teratogenic
risk in pregnancy
Take 400 g/day for
3 months prior to conception
5 mg/day (e.g. DM, obese,
previous NTD & thalassaemia)
Preconception counselling
Epilepsy
Diabetes Mellitus
Others
Figure 1
Ultrasound images
Intrauterinepolyp
Endometrioma
Hydrosalpinx
Figure 2
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Ovulation trigger
The ovulation trigger for final oocyte maturation is usually achieved by administering either Human chorionic gonadotropin
(HCG) or GnRH agonist in a cetrotide protocol. This is equivalent
of the mid-luteal LH surge that happens in natural cycle. In
addition to this, it also helps in resumption of meiosis in the
oocytes and thereby helping successful fertilization. Therefore it
is important to time ovulation trigger with clear instructions to
the patients.
Oocyte collection
Oocyte retrieval is usually done under sedation/general anaesthesia. TVUSS guided oocyte retrieval is scheduled 35.5 hours
after ovulation trigger. This is performed with a single-lumen 18gauge needle (Figure 5). All the follicles, even those less than 10
mm, are aspirated. The follicular fluid aspirated is received into
pre-warmed test tubes to avoid any wide fluctuation of temperature that can damage the meiotic spindles of the oocytes. This
fluid is then checked promptly by the embryologist in the laboratory to retrieve oocytes and transfer them to the culture medium under appropriate conditions in the incubator.
Box 1
Luteal support
The luteal phase in IVF cycles is insufficient because of pituitary
suppression. Therefore women are administered luteal phase
support to improve implantation rates and thus pregnancy rates.
A recent Cochrane review showed that the live birth rate was
significantly higher with the progesterone for luteal phase support in IVF/ICSI cycles, favouring synthetic progesterone over
micronized progesterone. The addition of other substances such
as oestrogen or HCG did not seem to improve outcomes. There is
no evidence, thus favouring a specific route or duration of
administration of progesterone.
Ovarian stimulation
Ovarian stimulation is achieved usually by exogenous gonadotropins. There are currently two preparations in the market: the
first one extracted from urine of postmenopausal women (human
menopausal gonadotropins, HMG) and the second one being
recombinant gonadotropins. There is no evidence of difference in
effectiveness between urinary derived HMG and recombinant
FSH preparations in ART outcomes. Poor response is reported in
the range of 10e15% of patients. This is a major cause of cycle
cancellation and can be distressing to couples. In contrast severe
ovarian hyper-stimulation (OHSS) can occur in 0.5e2%of
women. Individualized stimulation protocols for IVF have been
introduced recently. This approach has been shown to be comparable to conventional ovarian stimulation in terms of live birth
rates however with less risk of ovarian hyper-stimulation and
multiple pregnancies.
Laboratory aspects
The oocytes are retrieved from the follicular fluid and transferred
to the culture medium under appropriate conditions in the
incubator. In this process, they are graded for maturity by the
embryologist. In IVF the oocytes are left in a small petri dish
along with prepared spermatozoa. In ICSI, the outer cumulus
cells are stripped from the oocyte before injection with single
sperm. Evidence of fertilization is checked 16e20 hours
following incubation or injection. The embryos are then incubated for a further 2e5 days for further development. The
embryologist grades them according to the number of cells, degree of fragmentation and regularity. The best embryos are
selected for transfer leaving any good quality embryos for
cryopreservation.
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Definition
Indication
Success
IVF
ICSI
Intra-cytoplasmic sperm
injection (ICSI) is where a
single sperm is injected
directly into an egg
Intrauterine insemination
(IUI) is when the fast-moving
sperm is separated from more
sluggish or non-moving sperm
and then inseminated inside
the uterus
Oligoasthenoteratozoospermia, poor
or failed fertilization, surgical sperm
retrieval, using frozen sperm and
embryo testing
Donor insemination, inability to have
vaginal intercourse because of a physical
disability or psychosexual problem,
BBV ve males to perform sperm
washing to reduce the risk
transmission of infection
DI
GIFT
Gamete intrafallopian
transfer (GIFT) uses the
healthiest eggs and sperm to
fertilize together in the
womans fallopian tubes
In vitro maturation (IVM) is
a process where the eggs are
removed from the ovaries when
immature. They are then matured
in the laboratory before being
fertilized
IUI
IVM
Table 2
Embryo transfer
The embryo transfer usually takes place on the fifth day after oocyte
retrieval. Embryo transfer is a simple procedure that requires a full
bladder and it is performed without sedation. A small, soft catheter
is loaded with the embryos and inserted through the cervix into the
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hCG trigger
Gonadotrophins
Day 1
menstruation
Oocyte
retrieval
SHORT PROTOCOL
hCG trigger
GnRH agonists
Gonadotrophins
Day 1
menstruation
Day 35
Oocyte
retrieval
Figure 3
more than two can be transferred. This is to avoid the risk of multiple
pregnancy and its sequelae. Any embryos left and of sufficiently
high quality are cryopreserved. There is clear evidence to suggest
that a single embryo transfer in each treatment cycle not only gives a
better cumulative pregnancy rate but also leads to significant
reduction in the worse perinatal outcomes associated with multiple
pregnancies.
Complications of ART
Success
The success rate of IVF depends on the age of the woman undergoing treatment, as well as the cause of the infertility
Antagonist protocol
Day 2
menstruation
Day 1
menstruation
Oocyte
retrieval
Figure 4
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Ovarian
ligament
Uterus
Fallopian
tube
Ovary
Follicle
Aspiration
needle
Uterine
cervix
Ultrasound
beam
Vagina
Ultrasound
probe
Collection
tube
Suction
pump
Figure 5
Multiple pregnancy
This is a major cause of perinatal morbidity and mortality in IVF
pregnancies. This is secondary to increased risk of prematurity,
preterm rupture of membranes and growth restriction and, its
long term sequelae. Multiple pregnancy is also associated with an
increased risk of maternal morbidity (pre-eclampsia, thromboembolic disease, ante partum and postpartum haemorrhage and
caesarean section). Multiple pregnancy rates are currently
around 20% for all IVF pregnancies. A target rate of <10% for
multiple pregnancies for all IVF pregnancies has now been set. It
is envisaged that using better embryo culture and selection
methods, and wider use of single blastocyst transfer could achieve this target. Below is the table comparing the pregnancy rate
between double and single embryo transfer (Table 3).
Good prognostic
factors
Bad prognostic
factors
Age < 30
Previous pregnancy
BMI 1930
Unexplained infertility
Figure 6
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Pregnancy
rate (2013)
eSET
(blastocyst 2013)
Multiple
pregnancy rate
(eSET 2013)
Multiple pregnancy
rate (DET 2013)
18e34
35e37
38e39
40e42
43e44
45 years
All ages
40%
36%
30%
33%
23%
8%
34%
47%
44%
37%
27%
27%
27%
45%
>2%
>2.5%
>2.5%
>2.5%
>2.5%
>2.5%
>2%
47%
45%
41%
35%
23%
23%
43%
40%
35%
28%
24%
16%
16%
35%
Table 3
C
C
C
C
C
C
Clinical signs
C
C
C
C
C
C
C
C
Laboratory findings
Weight gain
Hypovolaemia
Low blood pressure
Enlarged ovaries on ultrasound scan
Ascites e clinical/ultrasound
Thromboembolism (specially upper body
veins)
Pleural effusion
Pericardial effusion
C
C
C
C
C
C
C
Haemoconcentration
Leucocytosis
Electrolyte imbalance
Hypoalbuminaemia
High liver enzymes
Low creatinine clearance
Hypercoagulability
Table 4
Classification of OHSS
Ovarian size
Mild
<8 cm
Moderate
8e12 cm
Severe
>12 cm
Mild pain/discomfort
Abdominal swelling
Abdominal pain/discomfort,
Nausea/vomiting
Ascites (USS)
Pain, dyspnoea/tachycardia
Oedema
Oliguria
Ascites (Clinical/USS)
Pleural effusion
Table 5
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Management of OHSS
Analgesia
Paracetamol or co-codamol (avoid NSAIDs)
Parenteral opiates may be required but the patient must be
reviewed to exclude additional pathology (ovarian cyst
rupture, haemorrhage or torsion, etc).
Antiemetics
Metoclopramide or prochlorperazine
Thromboembolic prophylaxis
TED stockings
Prophylactic subcutaneous Fragmin should be considered
for all admitted patients e 2500 IU subcutaneously daily
or, if more severe, may need 5000 IU.
Formal anticoagulation is reserved for those cases with
clinical evidence of thromboembolism.
Cancer
There is no direct association between infertility management
regimens used and the development of invasive cancer. The
ovulation induction/stimulation agents should be used to the
lowest effective dose and duration. Women should be counselled
regarding the uncertainty of the current evidence and that there
may be increased risk of borderline tumours.
Fetal and neonatal complications
There is no evidence of increased risk of childhood illnesses or in
neuro-developmental or psychomotor developmental problems
in IVF babies. There is inconclusive evidence that IVF/ICSI may
increase the risk of particularly imprinting disorders. Certain
genetic and developmental defects have been reported in a very
small number of children born using ICSI treatment. It is still not
clear whether these risks are associated with the procedure or to
inherent sperm abnormalities. Undescended testis and urogenital
anomalies were reported in boys conceived by ICSI. A recent
study (2013) of 106,013 children born after assisted conception
found no increased risk of cancer in ART children. Long-term
safety of new technologies that are being introduced should be
established by setting up a national database.
Oocyte donation
Fluid balance
Oral fluids should be encouraged for all patients
Intravenous fluids reserved for patients who are admitted
(2e3 litres/day)
If urine output <700 ml/24 hours e catheterise and
monitor hourly urine volumes.
Indications for oocyte donation include premature ovarian failure, gonadal dysgenesis, poor egg quality and diminished
ovarian reserve. This should be discouraged if there are underlying medical problems. The risk of genetic abnormalities in the
offspring of women undergoing oocyte donation relates to the
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REVIEW
age of the donor. Appropriate counselling of all couples considering these procedures should be arranged prior to embarking on
the process.
Surrogacy
This is defined as Another woman carries and gives birth to a
baby for the couple who want to have a child. Some of the indications for surrogacy include recurrent miscarriages, uterine
malformations and repeated IVF implantation failures. The HFEA
does not regulate surrogacy. In the UK, the surrogate will be the
legal mother of the child unless or until parenthood is transferred
to the intended mother through a parental order. It is advised that
the couple should seek legal advice before proceeding with this
option. Surrogacy UK is a non-profit organization offering support and information to anyone with an interest in surrogacy
within the UK.
A
Practice points
C
FURTHER READING
Fertility: assessment and treatment of people with fertility problems
NICE clinical Guideline (CG156). 2013, http://www.nice.org.uk/
guidance.
Human Fertilisation and Embryolgy authority. http://www.hfea.gov.uk/.
Improving outcomes for fertility patient: multiple births. HFEA, 2015.
Mahmoud Mohammed K, Punukollu Durgadevi, Mahmood Tahir.
In vitro. Fertilization. Obstet Gynaecol Reprod Med 2013; 23:
238e46, http://www.obstetrics-gynaecology-journal.com/.
van Loendersloot Laura, Repping S, Bossuyt PMM, van der Veen F,
van Wely M. Prediction models in in vitro fertilization; where are
we? A mini review. J Adv Res May 2014; 5: 295e301.
C
C
209
ETHICS/EDUCATION
Shilpa Nambiar
Abstract
Magnesium sulphate has been established as an effective maternal
neuroprotective agent in pre-eclampsia and eclampsia and evidence
has shown that antenatal administration to mothers at risk of preterm
delivery reduces the risk of perinatal cerebral injury and subsequent
cerebral palsy and gross motor dysfunction. This article examines
the available evidence, its interpretation and its translation into clinical
practice.
Introduction
Cerebral palsy (CP) is a symptom complex of non-progressive
motor impairment syndromes secondary to brain injury or
anomalies arising in early development. The prevalence is estimated at 2 per 1000 live births, with a quarter of these attributed
to prematurity under 34 weeks. Improved neonatal facilities have
improved survival rates but has increased the incidence of cerebral palsy in survivors.
The aetiology for CP is multifactorial but very low birth
weights and extreme prematurity account or up to a third of
cases. The premature brain is exquisitely sensitive to white
matter injury because of vascular instability of the germinal
matrix leading to haemorrhage, hypoxia and subsequent cytokine and free radical activation. The most frequently observed
abnormalities associated with CP are peri-intraventricular haemorrhages (PIVH) and periventricular leukomalacia (PVL). Both
these complications affect the pyramidal tracts of lower extremities and lead to spastic CP of the legs.
PIVH originates in the vascular bed of the germinal matrix, an
area or fetal brain that completely disappears as the fetus matures. Hence, the incidence of CP decreases significantly with
increasing gestation: 14.6% at 22e27 weeks, 6.2% at 28e31
weeks, 0.7% at 32e36 weeks and 0.1% at term.
222
ETHICS/EDUCATION
CP/death risk
ACTOMgSO4,
Crowther et al. (1062), 2003
PREMAG, Marret
et al. (564), 2007
BEAMs, Rouse
et al. (2241), 2008
MAGNet, Mittendorf
(149), 2002
4 g bolus, 1 g/hour
4 g bolus
MAGPIE, Collaborative
Group (1544), 2002
6 g bolus, 2 g/hour
with retreatment
4 g bolus, 2e3 g/hour
(tocolysis) 4 g bolus
(neuroprotection)
4 g bolus, 1 g/hour or
5 g IM every 4 hours
Table 1
Conclusion
Despite all the unanswered questions, there is substantial data to
support the use of magnesium sulphate as a tool to reduce the
risk of morbidity from preterm births. It is hoped that there will
be more acceptance once results from ongoing studies are
available.
A
FURTHER READING
Doyle LW, Crowther CA, Middleton P, Marret S. Antenatal magnesium
sulfate and neurological outcome in preterm infants: a systematic
review. Obstet Gynecol 2009; 113: 1327e33.
Magnesium sulphate for fetal neuroprotection: guidelines consensus
group. J Obstet Gynaecol Can 2011; 33: 516e29.
Royal College of Obstetricians and Gynaecologists Scientic Impact
Paper No. 29: Magnesium Sulphate to Prevent Cerebral Palsy
Following Preterm Birth, Aug 2011.
223
CASE-BASED LEARNING
Mamoun Bereir
Carol Coughlan
Abstract
Subfertile couples by denition require medical help to get pregnant
after trying unsuccessfully for a variable period of time. Although the
term subfertility is also occasionally used in the context of women
who can conceive, but suffer recurrent miscarriages, this broad aspect
is outside the scope of this chapter. Subfertility can seriously affect
mental and social well-being, although not generally viewed as a disease that signicantly causes physical ill health. On the contrary, subfertility may in fact be the early manifestation of serious co-existing
disease. Advances in assisted reproductive technology in the last 25
years have simplied and diversied treatment options, thereby
rendering the terms infertility and sterility unfashionable. As a result,
there is now an unfortunate trend for couples to be subjected to supercial medical history and only perfunctory physical examinations, occasionally missing the presentations and implications of associated
co-morbidities, with devastating implications. There are now many
guidelines on the initial investigations and subsequent management
of the subfertile couple. It is therefore now relatively easy to assist a
couple to achieve a pregnancy. However, dealing with the devastating
news of causative factors like azoospermia, genetic disease, congenital anomaly or premature ovarian failure can be very difcult. To
discuss these sympathetically, professionals require interpersonal
skills in breaking bad news. Finally, a multidisciplinary team approach
should be adopted to cater for the long-term health consequences,
whenever co-morbidities are detected.
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CASE-BASED LEARNING
Case 1
25%
Miss NW, aged 34 years and her partner Mr JG, aged 41 years,
were referred to the local teaching Hospital from the district
Hospital on account of secondary subfertility due to tubal disease
of 12 months duration. They had been together for over two
years. Coital frequency was at best twice a week because of the
association with deep dyspareunia. Miss NW had a child aged 10
years from a previous relationship who lived with them. She had
separated from her previous partner because of infidelity
resulting in Chlamydia pelvic inflammatory disease, which was
eventually treated after some delay in diagnosis. She was on folic
acid, immune to Rubella, up to date with her cervical smear tests
and had been advised to cut down on alcohol and her 25 cigarettes per day habit. Hysterosalpingogram (HSG) performed at
the referring hospital showed bilateral large hydrosalpinges, with
no peritoneal spillage on either side. All other fertility tests were
normal. The couple had been told by the referring doctor that she
had two options of definitive treatment; either tubal surgery or
in-vitro fertilisation (IVF).
What initial advice would you give to this couple?
What is your opinion about the choice of tubal patency test
in this case?
What are the treatment options?
Pre-conception advice about diet, weight reduction, sensible
use of alcohol, cigarette cessation and prophylactic folic acid is
good practice during the first visit. Many couples also need to be
advised on a coital frequency of about 3 times a week, not timed
to ovulation unless medically indicated.
Most gynaecologists will disagree with the choice of HSG as
the test of tubal patency for this patient. Whenever there is a
reliable history of sexually transmitted disease (STD), or there
was co-existing pelvic pain or dyspareunia, diagnostic laparoscopy and dye test is certainly a better choice as it allows
assessment of the extent of tubal damage and inspection of the
peritoneum for adhesions or endometriosis. Diagnostic laparoscopy allows staging of the degree of tubal disease in order to
formulate a prognosis. For stage 1 (thin-walled with little or no
fibrosis) and 2 (thick-walled with good mucosa), laparoscopic
adhesiolyses and cuff salpingostomies performed at the same
time could offer a clinical pregnancy rate (CPR) of up to 50%
over three years; whereas, for stages 3 (thick-walled with marked
mucosal damage, or a thick fibrous endosalpingeal adhesion)
and 4 (tubo-ovarian mass or fibrosis, or an adherent hydrosalpinx with incarcerated ovary and/or isthmic damage), the
rates over the same period were less than 12%. Furthermore,
ectopic pregnancy rates after tubal surgery for stages 3 and 4
were as high as 25%.
The other treatment option was IVF. However, there is evidence that untreated hydrosalpinges or unilateral tubal disease,
which communicates with the uterine cavity, could significantly
reduce clinical pregnancy rates. Hydrosalpinges adversely affect
endometrial receptivity, thereby decreasing the implantation rate
and increasing the risk of early miscarriages. There is also evidence showing that laparoscopic salpingectomy or salpingectomies could more than double the live birth rate following IVF
to about 30% per cycle in good centres.
She underwent diagnostic laparoscopy and staging of tubal
disease, with additional consent to proceed to either adhesiolysis
30%
10%
20%
Male factors
Ovulatory disorders
Unexplained
15%
Tubal disease
Uterine/peritoneal
211
CASE-BASED LEARNING
Normal ranges
1.5
15
39
32
40
58
4
(1.4e1.7)
(12e16)
(33e46)
(31e34)
(38e42)
(55e63)
(3.0e4.0)
Case 2
A Polish couple were referred to a tertiary centre with a history of
inability to conceive of 24 months duration. Both were 28 years
old and in good health. Neither smoked cigarettes, but both
drank roughly 10 units of alcohol per week. Mrs AT had a regular
menstrual cycle, an up-to-date normal cervical smear test, body
mass index (BMI) of 27, was rubella immune and had screened
negative for Chlamydia infection. Physical examination was unremarkable. Her mid-luteal progesterone assay was 63 nmol/L.
Mr PT was in good health, worked as a doorman in a nightclub,
and at a building site during the day. He had never fathered a
child. He had a right inguinal herniorrhaphy performed in Poland
5 years previously. He denied any significant drug history. Semen
analysis showed azoospermia on two occasions. Examination
revealed a fit, muscular young man with a normal phallus.
Testicular volumes were about 15 mL bilaterally. The epididymis
and vas were easily palpable bilaterally. No nodules or irregularity were detectable on either side.
Blood tests on Mr PT were reported as below.
Table 2
Testosterone
FSH
LH
Karyotype
Cystic fibrosis test
Table 3
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CASE-BASED LEARNING
deodorants from the age of 9 years. Furthermore, she had oligomenorrhoea, having only ever managed 2e6 menstrual cycles
per year. In the last 6 years, she had to regularly shave her face,
chest and limbs. Her other secondary sex characteristics were
normal. From the preceding year, her hair had started to recede
at the front. There was no significant family, social or drug history. She was clinically obese around her trunk (BMI 37), but
normotensive. Baseline tests carried out at their district hospital
were as shown below.
Semen analysis
HSG
Basal FSH
Basal LH
Testosterone (total)
SHBG
Case 3
A young couple was referred to the local tertiary centre for oligomenorrhoea and anovulatory subfertility probably due to
polycystic ovary syndrome. Mrs AT was 23 years old and
developed armpit hair by the age 8 years and had to use
Normal parameters
Normal cavity and bilaterally patent tubes
3.4 I.U./L (Normal range 2.5e10.2)
8.6 I.U./L (Normal range 1.9e12.5)
4.5 nmol/L (Normal range 0e2.5)
85 nmol/L (Normal range 20e109)
213
CASE-BASED LEARNING
Case 4
A couple were referred to a tertiary centre with a history of
inability to conceive of 24 months duration. Both were 39 years
old and in relatively good health. Neither smoked cigarettes and
alcohol intake for both was minimal. Mrs CD had a regular
menstrual cycle, an up-to-date normal cervical smear test, body
mass index (BMI) of 27, was rubella immune and had screened
negative for Chlamydia infection. She complained of severe
dysmenorrhoea predominantly on days one to three of her cycle
with acute exacerbation on day one. The pain is often associated
with gastrointestinal symptoms of vomiting and diarrhoea.
214
CASE-BASED LEARNING
What advice would you give this 39 year old woman with a
diagnosis of endometriosis and right tubal blockage?
Two main surgical strategies have been used; including
excision biopsy or ablation. Medical therapy or simple aspiration and irrigation of endometrioma are ineffective, with
recurrence rates greater than 80% at 6-month follow-up.
Removal of the cyst lining, by either stripping or sharp excision of the capsule is frequently easy and is the optimum
treatment, although, when impossible, cyst-wall ablation gives
comparable results. Following adhesiolysis, irrigation and suction procedure, the ovarian capsule is identified around the cyst
opening. Once the plane of cleavage is found the cyst wall is
easily stripped from the ovary. Occasionally, it may be necessary to incise at the centre of the cyst in order to identify a
cleavage plane. Care must be taken to preserve ovarian tissue
and closure of the ovary is not proven to be necessary. Too
superficial diathermy ablation may result in inadequate treatment, whereas over-enthusiastic treatment may destroy ovarian
cortex and reduce its function.
The patient should be advised to proceed with in vitro fertilization treatment. ART is effective in the treatment of infertility
in patients with endometriosis. There are reports of poorer
ovarian responses to stimulation and poorer outcomes of ART
cycles in women with advanced endometriosis. A luteal phase,
GnRH analogue long protocol has been shown to improve live
birth rate.
This patient proceeded to IVF treatment which unfortunately
was unsuccessful for her. She then decided to explore the option
of adoption.
A
Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease
in women due to undergo in vitro fertilisation. Cochrane Database
Syst Rev 2004. Issue 3. Art. No.:CD002125.
Marcoux S, Maheux R, Berube S, The Canadian Collaborative
Group on Endometriosis. Laparoscopic surgery in infertile
women with minimal or mild endometriosis. N Engl J Med
1997; 337: 217e22.
Menon DK. Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril 2003; 79(suppl 3): 1659e61.
NICE guideline. Investigations of fertility problems and management
strategies. In: Moody Jane, ed. Fertility assessment and treatment
for people with fertility problems. Guideline developed by the National Collaborating Centre for Womens and Childrens Health.
London: RCOG Press, 2004; 39e56.
Vanky E, DE Zegher F, Diaz M, Ibanez L, Carlsen SM. On metformins
potential to prevent preterm delivery in women with polycystic
ovary syndrome - an epi-analysis. Acta Obstet Gynecol Scand
2012 Sep 24; http://dx.doi.org/10.1111/aogs.12015 (Epub ahead of
print).
Practice points
C
FURTHER READING
Balen AH. Management e diagnosis and treatment. In: Infertility in
practice. 3rd edn. London: Informa Healthcare, 2008; 123e288.
Camus E, Poncelet C, Gofnet F, et al. Pregnancy rates after in-vitro
fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies. Hum
Reprod 1999; 14: 1243e9.
Dover RW, Torode H. Endometriomas: a review of modern management. Gynaecol Endosc 2000; 9: 219e26.
Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline:
management of women with endometriosis. Human Reprod 2014;
29: 400e12. http://dx.doi.org/10.1093/humrep/det457. Epub 2014
Jan 15.
215
SELF-ASSESSMENT
Self-assessment questions
Questions
D)
E)
F)
G)
H)
Question 1 (SBA)
A 51-year-old woman with a BMI of 44 is diagnosed with an
early stage endometrial cancer at hysteroscopy performed for
chaotic perimenopausal bleeding. She attends the gynaecology
oncology clinic to discuss her condition and plan her treatment. She is very anxious and has searched extensively on the
internet for information about endometrial cancer before
meeting with you. Which one of the following statements is
true regarding her potential treatment?
A) Adjuvant radiotherapy provides no survival benefit in
women with early stage endometrial cancer.
B) Pelvic lymphadenectomy has an established therapeutic
benefit in women with early stage, low grade endometrial
cancer.
C) Systemic progestogens have a role in adjuvant treatment
following surgery for endometrial cancer.
D) For young women, in whom complete response has been
achieved with systemic progestogens, follow up with 6
monthly hysteroscopies should be recommended when
child bearing is complete.
E) Women with menopausal symptoms following surgery for
endometrial cancer should never be prescribed Hormone
Replacement Therapy.
I) Vitamin D
i) Occasionally used for symptomatic treatment of PCOS
symptoms in difficult or refractory cases, however long
term use can lead to bone demineralization, hot flushes,
and atrophic vaginitis.
ii) Indicated as an adjunct treatment to protect long-term
health in patients with premature ovarian failure.
iii) Therapy used to treat children with precocious puberty
due to radiation.
iv) Increases the ovulation rate by decreasing circulating
androgen levels.
Question 4 (EMQ)
Which one of the following ovarian pathologies best fits the
descriptions given below?
A) Benign immature teratomas
B) Hypogonadotropic hypogonadism
C) Polycystic ovarian syndrome
D) KISS1R mutation
E) Germ cell tumour
F) Dysfunctional uterine bleeding
G) Ovarian cyst
H) Kisspeptin 1 mutation
I) Gonadal dysgenesis
J) Malignant immature teratomas
K) MKRN3 mutation
Question 2 (SBA)
Which one of the following statements regarding risk factors
for developing endometrial cancer is correct?
A) Obesity increases the risk of type 2 endometrial cancers.
B) The BRCA1 mutation is an established risk factor for
endometrial cancer.
C) Tamoxifen use is associated with an increase in the risk of
endometrial cancer and women prescribed this medication
should have regular screening for endometrial pathology.
D) Hysterectomy and bilateral salpingo-oophorectomy is not
of benefit to reduce cancer risk for women with confirmed
HNPCC.
E) Endometrial cancer is the most common female cancer in
the United Kingdom.
Question 3 (EMQ)
The following agents may have roles in managing peripubertal gynaecological problems. For each of the scenarios
below, choose drug that best fits the description given:
A) Medroxyprogesterone
B) Norethindrone
C) Cyproterone
Question 5 (SBA)
1. A 28-year-old patient with PCOS-associated infertility is
undergoing her second round of IVF treatment. During the first
cycle she experienced severe OHSS, followed by a miscarriage
of a twin pregnancy. She is anxious to avoid the possibility of
OHSS occurring again. Which one of the following strategies
would NOT be helpful to reduce the risk of OHSS?
A) Using low-dose stimulation protocol IVF
B) Follicular monitoring
C) Utilising GnRH analogue cycles rather than GnRH
antagonists
D) Utilising progesterone instead of HCG for luteal support
Flutamide
GnRH analogues
Metformin
Spironolactone
Growth hormone
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SELF-ASSESSMENT
Question 10 (SBA)
A 6-year-old girl is referred to the gynaecology clinic because
of concerns from her parents and GP regarding the development of secondary sexual characteristics, including pubic hair
and breast development. Which one of the following investigations would NOT form part of your work-up for this
patient?
A) Pelvic ultrasound scan
B) Bone age assessment
C) MRI head
D) Serum gonadotrophin levels
E) Diagnostic laparoscopy
Question 7 (SBA)
A 22-year-old woman with a BMI of 36 is referred to the
reproductive medicine clinic by her General Practitioner for
advice about her irregular periods. At her initial clinic visit,
several investigations are performed. Which of the following
findings would not be in keeping with the possible diagnosis
of polycystic ovarian syndrome?
A) A free androgen index (FAI) of 5.6
B) Clinically evident hirsutism across the chest and upper back
C) First menses at 8 years
D) No cortisol suppression during overnight dexamethasone
suppression test
E) Endometrial thickening of 16 mm on transvaginal ultrasound scan
Self-assessment answers
Answer 1
A. Adjuvant radiotherapy provides no survival benefit in
women with early stage endometrial cancer.
No study of adjuvant radiotherapy has demonstrated significant survival benefit for women with at low or intermediate
risk of recurrence. Whilst radiotherapy has been shown to
reduce the risk of recurrence (relative risk reduction 72%) this
does not translate into a reduction in the risk of death for these
women. The ASTEC trial, a multinational study of 1400 patients with early stage endometrial cancer, failed to show any
benefit from lymphadenectomy in terms of overall survival or
disease-free survival. A study of more than 500 patients
(Benedetti Panici P, Basile S, Maneschi F, et al.) reached
similar conclusions. Critics have highlighted several potential
flaws with the ASTEC study, as outlined in the main text, and
debate continues, however present evidence does not support
a therapeutic advantage of lymphadenectomy for women with
early stage disease. Systemic progestogens have a role in the
management of women unfit for other types of treatment or in
the palliation of advanced disease however there is no role for
progestogens in adjuvant therapy due to the often partial and
short lived effect of hormonal treatment. There is no evidence
that oestrogen only HRT adversely affects survival in women
following completion of treatment management for early stage
disease and as such, oestrogen replacement may be prescribed
for those women experiencing distressing menopausal symptoms following appropriate discussion regarding risks and
benefits.
Question 8 (SBA)
A 38-year-old woman and her 44-year-old partner attend the
reproductive medicine clinic with secondary infertility of 5
years. During the investigations, the male partner admits to
using performance-enhancing anabolic steroids to aid his
career as a professional rugby player. Which of the following
health risks should you warn him about?
A) Testicular cancer
B) Liver tumours
C) Reduced libido
D) Increased bone demineralisation
E) Migraines
Question 9 (EMQ)
Chose the fertility treatment option that is most suitable for the
cases outlined below:
A) In vitro fertilisation
B) In vitro maturation
C) Gamete intra-fallopian transfer
D) Donor insemination
E) Intrauterine insemination
F) Intra-cytoplasmic sperm injection
G) Ovulation induction
H) Ovarian drilling
Answer 2
A. Obesity increases the risk of both type 1 and type 2
endometrial cancers.
Obesity is a significant risk factor for endometrial cancer and is
strongly implicated in the rising incidence of the disease. Whilst
obesity is predominantly associated with type 1, oestrogen
225
SELF-ASSESSMENT
Answer 5
C. Utilising GnRH analogue cycles rather than GnRH
antagonists
Use of GnRH antagonists for pituitary suppression have
been associated with lower risk of OHSS by 40% and cycle
cancellation compared with GnRH agonist protocols. The
other options are all associated with a lower risk of developing
OHSS.
Answer 6
C. Centrosome
While the oocyte is the major contributor to the new
conceptus, the spermatozoan provides several key components including the male pronculeus and the centrosome.
Answer 7
D. No cortisol suppression during overnight dexamethasone suppression test
The other options here could all be in keeping with the
diagnosis of PCOS, however failure to suppress cortisol with
an overnight dexamethasone suppression test implies a
possible diagnosis of Cushings syndrome and therefore warrants a referral to endocrinology before proceeding with
treatment.
Answer 3
i. E
These symptoms arise from oestrogen deficiency, which is
a risk of long-term GnRH use.
ii. I
Vitamin D supplementation is often prescribed along with
calcium to prevent osteoporosis in women with premature
ovarian failure.
iii. H
Children with precocious puberty due to radiation often
have specific deficiency of growth hormone.
iv. G
Metformin is a biguanide used in the treatment of type II
diabetes. It was first observed that women taking metformin
plus clomiphene had more frequent ovulation than women
taking clomiphene alone. Metformin is used for the induction
of ovulation.
Answer 8
B. Liver tumours
Prolonged use of anabolic steroids can cause abnormal
liver enzymes, cholestasis or liver tumours. Increased libido is
likely with anabolic steroid use, but is concurrent with suppressed spermatogenesis.
Answer 9
1. F. Intra-cytoplasmic sperm injection
Sperm can be retrieved in this situation and injected into
the cytoplasm of the egg. The success rates of this procedure
are similar to those of IVF.
2. E. Intrauterine insemination
Use of this technique would allow sperm washing to reduce
the risk of HIV transmission to the female partner. From the
information given, there does not appear to be any additional
need for any fertility treatment for either partner.
3. B. In vitro maturation
This technique allows the collection of immature eggs from
the ovaries, which are then matured in vitro prior to fertilization. It reduces the risk of developing OHSS, but it is also
likely that there will be fewer eggs collected.
Answer 4
i. C
Polycystic ovarian syndrome has implications for reproductive and metabolic health throughout life, and this is
important to bear in mind during pregnancy.
ii. B
The most common causes of primary amenorrhoea are
gonadal dysgenesis (50%), hypogonadotropic hypogonadism
llerian agenesis (15%), transverse vaginal septum
(20%), mu
or imperforate hymen (5%), and pituitary disease (5%).
iii. G
The most common cause of peripheral precocious puberty
in girls is a large functional ovarian follicular cyst.
iv. K
Familial cases of central precocious puberty have been
attributed to paternally transmitted inactivating mutations of
the MKRN3 gene. Gain of function (not loss of function) mutations in Kisspeptin and KISSR are also associated with precocious puberty.
Answer 10
E. Diagnostic laparoscopy
The other investigations listed will often form part of the
recommended panel to diagnose precocious puberty. An examination under anaesthesia may also be indicated, but laparoscopy would rarely need to be performed.
226