Female Infertility Flashcards
Define infertility
- an inability to conceive after 12 months or more of unprotected sexual intercourse (WHO 2009)
How many couples have difficulty conceiving?
Difference between primary and secondary infertility?
- 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)
What is the percentage attributable to female factors?
- 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
Give the aetiology of female infertility (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
What is endometriosis? How common? Definition and pathology?
Symptoms?
- 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
Diagnosis of endometriosis
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
Evidence for non-invasive test for endometriosis
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
Treatment of endometriosis
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).
Alternative treatments for endometriosis
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.
Evidence for selective progesterone receptor modulators
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
What is polycystic ovary syndrome?
Prevalence?
- 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
What is the pathophysiology of PCOS?
- 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
Evidence of pathophysiology relating to follicular AMH levels
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
Evidence for AMH in ovarian follicles
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.
Evidence that AMH works by inhibiting FSH sensitivity
Pellat et al., 2011
- Granulosa cells were exposed to AMH with and without gonadotropins
- RT-PCR showed AMH reduced FSH receptor mRNA expression.
- AMH inhibits factors affecting FSH sensitivity. The AMH overproduction in anovulatory polycystic ovaries (PCO) may therefore restrict folliculogenesis by an inhibitory effect on FSH sensitivity, thereby contributing to anovulation.
