How to Manage Weight Loss in Women With Obesity and PCOS Seeking Fertility?

Jonathan M. Hazlehurst; Pushpa Singh; Gurkiran Bhogal; Sophie Broughton; Abd A. Tahrani

Clin Endocrinol. 2022;97(2):208-216.

Abstract and Introduction

Abstract

Obesity exacerbates the phenotype of polycystic ovarian syndrome (PCOS) including infertility as well as reducing the efficacy and access to fertility treatments. Weight management is, therefore, a key component of treatment for women with PCOS and coexistent obesity. Many women with PCOS describe significant difficulty losing weight and treatment options are limited. The first-line treatment is lifestyle interventions though the weight loss and any impact on fertility are limited. No one dietary strategy can be preferentially recommended based on current evidence. While very low energy diets can result in significant weight loss the evidence for impact on fertility is limited. Pharmacotherapy, including a range of treatments can result in marked weight loss and there is some evidence of improved rates of conception including spontaneous and in response to assisted reproduction treatment. As with pharmacotherapy, data regarding bariatric surgery is largely from nonrandomized studies and though the significant weight loss is anticipated to improve fertility the available data prevents firm conclusions. Clinicians and patients must consider the magnitude of weight loss to be targeted as well as the anticipated fertility treatment required and the timeline of treatment when deciding upon the personalized weight loss strategy. Clinicians and patients should be confident in targeting the most appropriate treatment early in the patient's management to avoid unnecessary delays.

Introduction

Polycystic ovarian syndrome (PCOS) affects 6%–10% of women of reproductive age.^[1] Obesity is a major contributor to subfertility in PCOS via its impact on hyperandrogenism, hyperinsulinaemia, inflammation, insulin resistance and the interplay between the hypothalamic–pituitary–ovarian axis, follicle development, oocyte quality and endometrial receptivity (Figure 1).^[2]

(Enlarge Image)

Figure 1.

An overview of the mechanisms linking PCOS and obesity that contribute to subfertility. PCOS and obesity can contribute to a proinflammatory, hyperinsulinaemic, insulin-resistant state that can drive subfertility both by the effects of the resulting hyperandrogenaemia as well as effects on the developing oocytes and the endometrium. IR, insulin resistance; LH, luteinizing hormone; PCOS, polycystic ovarian syndrome; SHBG, sex hormone-binding globulin

Obesity is associated with reduced reproductive outcomes regardless of the mode of conception (unassisted, ovulation induction, in vitro fertilization, intracytoplasmic sperm injection), a barrier for accessing assisted conception and is associated with adverse maternal and foetal outcomes.^[2]

Weight loss is an important treatment target in women with PCOS and obesity that are seeking fertility especially given that women with PCOS can lose similar amounts of weight to women without PCOS regardless of treatment modality despite earlier reports to the contrary.

Here, we provide a narrative review to support clinicians managing obesity in women with PCOS, obesity and subfertility. We have conducted a Medline search using a combination of specific search terms: obesity, weight loss, fertility, polycystic ovaries (or ovarian or ovary) syndrome, maternal outcomes, pregnancy outcomes, lifestyle interventions, low energy diet, low carbohydrate diet, low-fat diet, weight loss pharmacotherapy, antiobesity medication, bariatric surgery and the names of individual bariatric procedures in the title or abstract. We did not incorporate a body mass index (BMI) cut-off within the identified literature. We prioritized the reporting based on evidence hierarchy giving preference to systematic reviews (SRs), and randomized controlled trials (RCTs). While a multitude of studies have examined pharmacotherapy in PCOS we highlighted studies aimed at targeting weight loss that reported any fertility-related outcome.

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Table 1. Studies of pharmacotherapy in women seeking fertility
References	Population	Design	Intervention	Duration	Outcome
Kumar and Arora (2014)	n = 90	Open-label RCT	Common: Hypocaloric dietary and exercise advice	If spontaneously ovulating at end of intervention (3 months) where followed for pregnancy for 3 months or otherwise had one cycle of ovulation induction	Spontaneous ovulation
	Age < 40		Arm 1: Metformin 500 mg TID for 3 months		Arm 1: 23.3%
	BMI ≥ 23 kg/m²		Arm 2: Orlistat 120 mg TID for 3 months		Arm 2: 33.3%
	PCOS (Rotterdam revised 2003 criteria)		Arm 3: Advice only		Arm 3: 3.3%
					Conception rates
					Arm 1: 16.7%
					Arm 2: 40%
					Arm 3: 3.3%
					Weight change (%)
					Arm 1: 7.78 ± 0.57
					Arm 2: 7.81 ± 0.66
					Arm 3: 4.70 ± 0.26
Kort et al. (2014)	n = 52	Retrospective cohort	Common: Hypocaloric dietary and exercise advice	≥18 months	Weight loss
	Age = 33.49 ± 4.37		Metformin if FPG > 5.5 mmol/L or 2-h glucose > 7.8 mmol/L		33% lost ≥ 10%
	BMI = 33.17 ± 6.67 kg/m²		Phentermine^a could be added for ≤3 months when weight loss <10%		67% lost < 10%
	BMI ≥ 30 kg/m² 56%				14% Of women with PCOS lost ≥ 10%
	Seeking fertility and referred for weight management				Pharmacotherapy use
					Metformin, n = 38
					Phentermine, n = 20
					(neither had a significant effect on weight loss)
					Conception rates
					Women losing ≥ 10% = 88%
					Women losing < 10% = 54%
					p = .049
					Live birth rates
					Women losing ≥ 10% = 71%
					Women losing < 10% = 37%
					p = .024
Legro et al. (2015)	n = 149	Open-label RCT	Preconception interventions for 16 weeks	16 weeks of intervention followed by four cycles of clomiphene citrate	Weight
	Age = 18–40		Arm 1 'OCP': OCP		(Mean change from baseline [95% CI] at 16 weeks)
	BMI = 27–42 kg/m²		Arm 2 'Lifestyle': lifestyle modification consisting of caloric restriction with meal replacements, weight loss medication (either sibutramine, or orlistat), and increased physical activity to promote a 7% weight loss		Arm 1: −1.1 (−2.0 to −0.3)
			Arm 3 'Combined': 'Lifestyle' + 'OCP'		Arm 2: −6.2 (−7.1 to −5.3)
			Followed by		Arm 3: −6.1 (−7.0 to −5.2)
			Four cycles of ovulation induction with clomiphene citrate		Ovulation
					(total no. of ovulations/total treatment cycles)
					Arm 1: 71/154
					Arm 2: 82/136
					Arm 3: 94/140
					Clinical pregnancy
					(foetal heart motion visualized on ultrasound)
					Arm 1: 7/49 (14%)
					Arm 2: 13/50 (26%)
					Arm 3: 13/50 (26%)
					Live birth
					Arm 1: 5/49 (10%)
					Arm 2: 13/50 (36%)
					Arm 3: 12/50 (24%)
Nylander et al. (2017)	n = 72	Double-blinded RCT	Randomized in a 2:1 ratio to 26 weeks of:	26 weeks	Weight loss
	Age > 18		Arm 1: Liraglutide 1.8 mg QD (increased from 0.6 mg and 1.2 mg in first 2 weeks)		Liraglutide 5.2 kg
	BMI ≥ 25 kg/m²		Arm 2: Placebo		(95% CI: 3.0–7.5, p < .0001, compared to placebo)
	PCOS (Rotterdam revised 2003 criteria)				Difference at 6 months of bleeding ratio
	C-peptide > 600 pmol/L				(Number of menses/number of months
					(Mean [95% CI])
					Arm 1: 0.28 (0.20–0.36)
					Arm 2: 0.14 (0.02–0.26)
					p < .05
					Difference at 6 months of ovarian volume (ml)
					(Mean [95% CI])
					Arm 1: −2.0(–3.1 to −0.9)
					Arm 2: –0.2(–1.7 to 1.4)
					p = NS
Salamun et al. (2018)	n = 28	Open-label RCT	Common: Dietary advice	12 weeks	Weight loss
	Age = 31.07 ± 4.75		12 weeks, including titration periods to achieve:		Arm 1: 6.99 ± 6.02 kg
	BMI = 36.7 ± 3.5 kg/m²		Arm 1 'MET': Metformin 1000 mg BID		Arm 2: 7.51 ± 3.89 kg
	PCOS (Rotterdam revised 2003 criteria)		Arm 2 'COMBI': Metformin 1000 mg BID + Liraglutide 1.2 mg QD		p = NS
	First or second IVF attempt		Followed by IVF after 1 month of washout from pharmacotherapy		Pregnancies within 1 year
					Arm 1: 5 of 14 (1 spontaneously, 2 after IVF, 2 spontaneously after unsuccessful IVF)
					Arm 2: 9 of 13 (1 spontaneously, 6 after IVF, 2 spontaneously after unsuccessful IVF)
Liu et al. (2017)	n = 176	Open-label RCT	Arm 1: Exenatide 10 μg BID for 12 weeks	24 weeks	Weight loss at 12 weeks
	Age = 18–40		Arm 2: Metformin 1000 mg BID for 12 weeks		Arm 1: 4.29 ± 1.29 kg
	BMI ≥ 24 kg/m²		Common: Then 12 weeks of metformin 1000 mg BID only		Arm 2: 2.28 ± 0.55 kg
	PCOS (Rotterdam revised 2003 criteria)				p < .05
					Menstrual frequency ratio
					Arm 1: 0.62 ± 0.12
					Arm 2: 0.37 ± 0.01
					p < .01
					Natural pregnancy rates in the 12 weeks that followed the preconception phase followed the preconception phase
					Arm 1: 34/78
					Arm 2: 15/80
					p < .05

Note: Data are shown as mean ± standard difference unless otherwise stated.
Abbreviations: 2-h glucose, glucose at 2 h as part of oral glucose tolerance test; BID, twice a day; BMI, body mass index; FPG, fasting plasma glucose; IVF, in vitro fertilization; OCP, oral contraceptive pill; PCOS, polycystic ovary syndrome; QD, once a day; RCT, randomized controlled trial; TID, three times a day.
^aPatients given phentermine were asked to pause attempts at conception when on the medication.