Clomifene citrate

These recommendations are based on guidelines from the National Institute for Health and Clinical Excellence for people with fertility problems [NICE, 2004] and a review article [Balen and Rutherford, 2007].

• Anti-oestrogens, such as clomifene citrate and tamoxifen, occupy hypothalamic oestrogen receptors but do not activate them. This interferes with the binding of estradiol and thus prevents negative feedback inhibition of follicle-stimulating hormone secretion.
• Randomized controlled trials provide evidence from randomized controlled trials that clomifene citrate is effective at increasing pregnancy rates.
• Women may benefit from receiving clomifene citrate in up to 12 cycles, as cumulative pregnancy rates continue to increase after six treatment cycles before reaching a plateau similar to that of the normal fertile population by cycle 12. Alternative treatments should be considered after 12 cycles if results are poor [National Collaborating Centre for Women's and Children's Health, 2004]. This is because evidence suggests that the use of clomifene citrate for more than 12 cycles is associated with an increased risk of ovarian cancer.

Ovarian hyperstimulation syndrome (OHSS)

• Mainly retrospective and prospective studies provide evidence that women with polycystic ovary syndrome (PCOS) are at increased risk of developing OHSS. This is characterized by massive enlargement of the ovaries and ascites, that can lead to rapid and symptomatic enlargement of the abdomen, intravascular contraction, hypercoagulability, and systemic organ dysfunction [Legro, 2001].
• OHSS has been reported rarely in women who have taken clomifene citrate [Brown et al, 2005].

Laparoscopic ovarian drilling (LOD)

• There is evidence that LOD is less likely than gonadotrophin therapy to result in multiple pregnancies in the management of clomifene-resistant PCOS. However, LOD is effective in less than 50% of women, who then need to be treated with additional ovulation induction.
• LOD is recommended as a second-line option if ovulation induction with clomifene citrate has failed [Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008].
• The aim of surgery is to destroy ovarian androgen-producing tissue [Farquhar et al, 2007].
• Intraovarian androgen production decreases, which results in a decreased circulating androgen concentration. A reduction in total and free testosterone by 40–50% after LOD has been found [Pirwany and Tulandi, 2003].
• The destruction of the ovarian stroma seems to have an indirect modulating effect on the pituitary gland. Luteinizing hormone concentrations decrease and follicle-stimulating hormone concentrations tend to increase, thus restoring the normal luteinizing hormone/follicle-stimulating hormone ratio. This leads to recruitment of a new set of follicles and resumption of normal ovarian function [Pirwany and Tulandi, 2003].
• These endocrine changes occur rapidly after surgery and are sustained for several years [Pirwany and Tulandi, 2003]. However, there is ongoing concern about the long-term effects of LOD [Farquhar et al, 2007].
• During LOD, either laparoscopic ovarian cautery or laser vaporization (using CO₂, argon or Nd:YAG lasers) is used to create multiple perforations (about 10 holes per ovary) in the ovarian surface and stroma. The procedure can be done on a day-case basis. There is a risk of peri-adnexal adhesions, and LOD should only be offered as a second-line treatment for clomifene citrate-resistant anovulatory women [Pirwany and Tulandi, 2003; Farquhar et al, 2007].
• Ovarian wedge resection is no longer recommended. This was the first established surgical treatment for PCOS and has been used for years but is now obsolete because of the risk of post-surgical adhesions and the introduction of medical ovulation induction [Farquhar et al, 2007].

Gonadotrophins

• There is evidence that gonadotrophins are effective in inducing ovulation in anovulatory women with PCOS who have not responded to clomifene citrate.
• Gonadotropins require careful monitoring to reduce the risk of multiple pregnancy, and low-dose regimens are now used to prevent overstimulation and multiple pregnancies [Balen and Rutherford, 2007].
• Gonadotrophins are recommended as a second-line option if ovulation induction with clomifene citrate has failed [Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008].

Multiple pregnancy

• Women with PCOS are at increased risk of multiple pregnancy with both clomifene citrate and human menopausal gonadotrophin treatment [Balen and Rutherford, 2007].

Metformin

• A Cochrane systematic review found no evidence that metformin improves live birth rates when used alone or in combination with clomifene citrate.
• Expert opinion in a consensus workshop [Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008] and a non-systematic review [Balen and Rutherford, 2007] is that metformin is no longer recommended as first-line treatment in infertile women with PCOS. Its use should be restricted to women with glucose intolerance [Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008].