Female Infertility 2

Question 1

Define infertility

Answer 1

• an inability to conceive after 12 months or more of unprotected sexual intercourse (WHO 2009)

Question 2

How many couples have difficulty conceiving?

Difference between primary and secondary infertility?

Answer 2

• 1 in 7 couples have difficulty conceiving which approximates to around 3.5million people in the UK
• Primary is couples who have never conceived and secondary is couples who have previously conceived (NICE 2013)

Question 3

What is the percentage attributable to female factors?

Answer 3

• Factors causing infertility are attributable to both male and female with approximately 1/3 of infertility related to each gender (Centres for Disease Control and Prevention, 2009)
• Idiopathic in 25% of cases

Question 4

Give the aetiology of female infertility (4)

Answer 4

• Majority due to ovulation disorders such as PCOS or defective embryonic development of the gonads – 40%
• Defect in the tubal system which leads to impaired zygote transport are the second most common with diseases such as immotile cilia
• Endometriosis
• Problems with internal genitalia environment

Question 5

What is endometriosis? How common? Definition and pathology?

Symptoms?

Answer 5

• Common condition affecting 5-10% of women
• Most common in women of child bearing age and unlikely in women through the menopause (Mehedintu et al., 2014)
• Defined as ectopic endometrial type mucosa growing outside the uterus which the widely accepted mechanism for endometriosis is retrograde menstruation which was proposed in the 1920s by Sampson. The sloughed menstrual endometrium flows backwards via patent fallopian tubes and can access the peritoneal cavity where it can implant and cause endometriosis.
• It is an oestrogen dependent inflammatory condition that is often linked to the menstrual cycle
• Symptoms – pelvic pain, menstrual cramps, infertility, dysmenorrhoea and dysparenunia

Question 6

Diagnosis of endometriosis

Answer 6

The gold standard for diagnosis of endometriosis is a laparoscopy, a surgical procedure which allows visual confirmation as well as a biopsy to be taken for histological analysis.
Non-invasive tests have been studied to try and replace the laparoscopy with the same level of accuracy

Question 7

Evidence for non-invasive test for endometriosis

Answer 7

Hirsch et al., 2017

• A prospective observational cohort study, evaluating the diagnostic accuracy of serum cancer antigen Ca125, a known marker for ovarian epithelial cancer showed that a high serum Ca125 >30units/ml was able to detect endometriosis and correlated to severity of the disease however a low result <30units/ml was not conclusive enough to exclude endometriosis.
• One limitation was the exclusion of patients who had conditions which may raise Ca125, this obviously reduces the false-positive results– seemingly underscoring the need for further research and unreliably improving their results attained
• Although the study presents an argument for a less invasive rule-in diagnostic test, the study has design flaws and the results do not give a conclusive answer so laparoscopy with biopsies remains the gold standard

Question 8

Treatment of endometriosis

Answer 8

The treatments of endometriosis vary from pain control using NSAIDs, hormonal control aimed at reducing the level of oestrogen; inducing amenorrhoea suppresses lesion growth and associated symptoms.
Those women that do not respond to medical therapy can have laparoscopic surgery to ablated or remove the lesion of ectopic tissue which has been shown to improve fertility (Marcoux et al., 1997).

Question 9

Alternative treatments for endometriosis

Answer 9

There are assisted reproductive techniques (ART) available to endometriotic patients discussed later, however novel hormonal treatments such as mifepristone, a selective progesterone receptor modulators (SPRM) have been trialled to improve fertility rates in women.

Question 10

Evidence for selective progesterone receptor modulators

Answer 10

Xue et al., 2016

• Randomised control trial of 150 endometriotic patients 24 weeks of treatment, control (gestrinone) and mifepristine, the scores of pelvic symptoms, as discussed earlier, and clinical signs were significantly reduced to the control and there was no increase in adverse effects across the groups.
• Presumably this was a direct consequence of significantly reduced serum LH, FSH, oestrogen and progesterone levels.
• Pregnancy rates were identified on follow up and the rate of 72% after 12 months was significantly higher than in control groups.
• Highlight the efficacy of mifepristone in both treatment for endometriosis and improving fertility non-surgically and without the need for ART

Question 11

What is polycystic ovary syndrome?

Prevalence?

Answer 11

• Prevalence is 15-20% (European Society for Human Reproduction)
• Most common cause of anovulation

An endocrine disorder which leads to
o Hyperandrogenism
o Polycystic Ovaries
o Irregular Menses although up to 30% have normal menses

Question 12

What is the pathophysiology of PCOS?

Answer 12

• Poorly understood which may be impacting on the efficacy of treatments
• It is thought to be implicated by the existence of excess anti-mullerian hormone (AMH)
• AMH is a glycoprotein hormone produced by granulosa cells of ovarian follicles and in rats, AMH production coincided with oocyte meiotic arrest

Question 13

Evidence of pathophysiology relating to follicular AMH levels

Answer 13

Fallat et al., 1997

• A prospective study which showed that women with PCOS had higher serum and follicular fluid AMH levels
• Examination of patients receiving IVF showed an increase in immature oocytes retrieved in PCOS
• The higher follicular MIS level in PCOS patients correlating with a greater number of immature oocytes retrieved supports the contention that MIS suppresses oocyte maturation

Question 14

Evidence for AMH in ovarian follicles

Answer 14

Pellat et al., 2007

• Examined the production of AMH by cells from a range of follicle sizes from normal ovaries and PCOs. Granulosa cells (GCs) and theca and follicular fluid (ff) were isolated from intact follicles
• The mean level of AMH was 4x higher in granulosa cells from ovulatory PCOs and 75x higher from anovulation PCO
• In cells from PCOs, FSH significantly decreased AMH, and in contrast, LH increased AMH
• Could identify the hormone FSH as a potential therapeutic agent??
• The reduction of AMH in larger follicles from normal ovaries appears to be an important requirement for the selection of the dominant follicle. This increase in AMH may contribute to failure of follicle growth and ovulation seen in polycystic ovary syndrome.

Question 15

Evidence that AMH is higher in PCOS women

Answer 15

Homburg et al., 2013

• Strengthened this theory
• Significant increase in the mean serum AMH concentrations in women with PCOS than those with PCOM and control women.
• One limitation is that the study was restricted to women who sought out treatment for infertility so hard to extrapolate into whole population.
• The study suggests that the severity of symptoms of PCOS is positively related to the number of small follicles and that AMH

Question 16

Diagnosis of PCOS

Answer 16

• Rotterdam criteria – 2 of the following 3
  o Ovulatory Dysfunction (infrequent or absent)
  o Clinical or Biochemical androgenism
  o Polycystic Ovaries seen on USS

Question 17

Update on diagnosis for PCOS using AMH

Answer 17

• Update by Kelsey et al., 2013
  o Meta-analysis of studies using AMH as a possible diagnostic marker
  o Found specificity and sensitivity in diagnosing PCOS in the symptomatic women of 79.4% and 82.8%, respectively, for a cut-off value of AMH of 4.7 ng/mL
  o May be a useful initial diagnostic test however further validation using prospective population cohort studies are needed

Question 18

Further evidence for AMH in diagnosis of PCOS

Answer 18

• Dewailly et al., 2011
  o Also demonstrated the ability for AMH becoming a diagnostic marker which provided similar values in sensitivity and specificity
  o However, this study incorrectly excluded from the control group women with asymptomatic polycystic ovaries who may have increased AMH levels, thereby accentuating any difference

Question 19

Treatment for PCOS

Answer 19

Ovulatory Stimulation
- Weight Loss
- Metformin
Shown that AMH can be a predictor of response to treatment as very high levels in PCOS is associated with resistance to weight loss and metformin induction of ovary stimulation

Question 20

Evidence for use of exogenous FSH in improving fertility

Answer 20

Catteau et al., 2007

• Investigated whether a decrease in the serum AMH level was concomitant to the appearance of a dominant follicle induced by administration of mild amounts of exogenous FSH in women with PCOS
• Prospective study included 30 oligo-ovulatory women resistant to clomiphene citrate for six cycles
• Mean AMH relative values declined significantly and the mean FSH relative values increased from 91% to 107%
• Study would benefit from further control studies to compare the relative values against normal ovulation.

Question 21

What is chlamydia?
Incidence?
Symptoms and sequelae?

Answer 21

• Bacterial infection caused by Chlamydia trachomatis which is transmitted via contact with mucous membranes, commonly through sexual contact
• Most common bacterial STI with 200,000 new diagnoses made in 2015 (Public Health England)
• ¾ of women are asymptomatic and thus untreated which can lead to sequelae such as pelvic inflammatory disease (PID) due to ascension up the genital tract
• A high cause of tubal infertility, which occurs by damage to the tubes which impedes transport of ovum

Question 22

What are the two paradigms implicated in pathogenesis of chlamydia?

Answer 22

Immunological and cellular paradigm

Question 23

What is immunological paradigm?

What is the contradictory evidence about this theory?

Answer 23

• Immunological paradigm by an autoimmune reaction caused by cross reactivity to human proteins
• However, Hjelholt et al., 2011
• Enzyme-linked immunosorbent assay to analyse serum levels of antibodies
• Serum levels of antibodies against HSP60 from C. trachomatis were elevated in patients with TFI compared with controls. Levels of antibodies against human homologue of HSP60 did not differ between groups
• No connection was observed between TFI and antibodies to human HSP60, pointing to an infectious rather than an autoimmune inflammation as the cause of TFI

Question 24

What is the cellular paradigm?

And what is the evidence for it?

Answer 24

• Chlamydia initiates a pro-inflammatory response in non-immune host epithelial cells which was seen in vitro in epithelial cells (Rasmussen et al., 1997) and in vivo in murine models of chlamydia infection (Darville et al., 2001)
• Dessus-Babus et al., 2002
• Cells infected with chlamydia showed an increase in expression of mRNA IL-11, using RT-PCR.
• One hypothesis to explain this is that the immunosuppressive effects of IL-11 may allow the infection to escape host innate defenses for better dissemination

Question 25

What is the diagnosis for chlamydia?

Answer 25

• Risk Assessment of tubal pathology
  o C.trachomatis immunoglobulin testing (CAT) in serum – identifies women with previous CT infection
• Another test is the hysterosalpingograpghy
  o A contrast X-ray exam which can identify tubal blockage
• Laparoscopic investigation can be used for assessing tubal infertility
  o This test is invasive, expensive and carries surgical risks
  o Should be reserved for inconclusive tests

Question 26

Evidence for use of c.trachomatis immunoglobulin testing (CAT)

Answer 26

o Veenemans et al., 2002
 Compare likelihood of abnormal Chlamydia trachomatis antibody test results with abnormal hysterosalpingography (HSG) test results.
 Anti-C. trachomatis immunoglobulin G antibodies determined by indirect fluorescent antibody technique
 The positive likelihood ratio for C. trachomatis antibody testing was 1.8. This was comparable with the HSG, which had a positive likelihood ratio of 1.7.
 The predictive value of C. trachomatis antibody testing was equal to that of HSG, but ratios of 1.7 and 1.8 indicate a poor test so have a poor predictive value
 CAT causes minimal inconvenience to the patient which is why it should be maintained for use

Question 27

Treatment for chlamydia

Answer 27

• Ongoing infection treated with azithromycin and doxycycline

Question 28

What is the treatment for tubal damage caused by chlamydia?

Answer 28

o Chu et al., 2015
o Meta-analysis of studies assessed the success rate of salpingostomy, showed clinical pregnancy rate was 27% after salpingostomy with pregnancy rates increasing each year after the surgery
o The studies included are clinically heterogeneous in many aspects including patient characteristics, surgical technique and duration of follow-up after salpingostomy – so caution should be taken.

Question 29

What is ART and what percentage of successful live births occur?
Any risks associated with it?

Answer 29

This term includes all techniques which involve retrieving oocytes from the ovary such as IVF. According to the NHS, in 2010 the percentage of IVF treatments that resulted in a live birth was 32.2% for women under 35. There is a risk of multiple births, around 20x increase compared to natural pregnancies.

Question 30

Describe process of IVF

Answer 30

This process involves stimulating the ovary medically to produce oocytes, drugs include clomiphene citrate or newer, previously mentioned GnRH. Oocytes are then retrieved from the follicles and sperm sample is collected to obtain the most motile sperm. Introduced to the egg and allow fertilisation to happen.

Question 31

Evidence for use of IVF in endometriosis

Answer 31

Dong et al., 2013
Retrospective cohort study to compare IVF outcomes of women with endometriosis to those with tubal factor infertility who underwent IVF during the same period.
Endometriosis responded worse to ovarian stimulation than patients with tubal factors, reduced oocyte/embryo quality, impaired implantation, patients with endometriosis obtained acceptable IVF outcomes, as indicated by similar clinical pregnancy rate and live birth rate
IVF can be considered as an effective approach for managing endometriosis-associated infertility.

Question 32

Describe ICSI

Answer 32

ICSI – ART technique where single sperm is injected directly into egg, overcomes male infertility and tubal factors in women. After the procedure, the oocyte will be placed into cell culture and checked on the following day for signs of fertilisation

Question 33

Evidence for use of ICSI in chlamydia

Answer 33

Alshafi et al., 2013
Cross sectional study that showed intracytoplasmic sperm injection (ICSI) had a 32% success rate in patients with tubal infertility which is similar to other factors of infertility.
Gaudoin et al., 1999
Cross-sectional study with women who underwent oocyte recovery procedures for IVF cycles having vaginal swab specimens analysed with ELISA serology for Chlamydia
Seropositivity for Chlamydia species associated with tubal disease. There was no difference in pregnancy rates in any of the groups regardless of their serologic status for chlamydial infection.
Shows that women who have been treated for chlamydial infection in past achieve pregnancy rates with IVF treatment similar to those of women who have no evidence of such infections.
Suggests the viability of using this technique to help fertility rates.
Could fail – egg donation, adoption, surrogacy, counselling

Question 34

Papers in the Intro

Answer 34

WHo 2009
NICE 2013
Centre for disease control and prevention 2009

Question 35

Papers on Endometriosis - 5

Answer 35

Mehedintu 2014
Sampson 1920s
Hirsch 2017
Marcoux 1997
Xue 2016
Dong 2013

Question 36

Papers on PCOS - 7

Answer 36

European Society for Human Reproduction
Fellat 1997
Pellat 2007
Pellat 2011
Kelsey 2013
Dewailly 2011
Catteau 2007

Question 37

Papers on Chlamydia - 9

Answer 37

Public Health England 2015
Hjelholt 2011
Rasmussen 1997
Darville 2001
Dessus-Babbus 2002
Veenemens 2002
Chu 2015
Alshafi 2013
Gaudoin 1999