Key highlights
While there are no FDA-approved treatments specifically for PCOS, medications like Ozempic and Metformin are frequently prescribed off-label to aid symptom management.
PCOS, affecting 15-20% of reproductive-age women, is a complex syndrome linked to metabolic, hormonal, and reproductive health challenges, varying significantly among individuals.
Both Metformin and GLP-1 agonists show promise in addressing insulin resistance and weight management in PCOS, though each operates through different mechanisms.
Treatment decisions for PCOS often require individualized approaches to effectively address the syndrome's diverse symptoms, including metabolic, hormonal, and reproductive concerns.
Background
Lately, there’s a lot of hype in the media regarding GLP-1 receptor agonists, more popularized under the brand name Ozempic.
Aside from the raving celebrity testimonials, GLP-1 agonists have shown a great deal of success in patients experiencing metabolic disorders and obesity, commonly associated with PCOS (polycystic ovarian syndrome). But does this make GLP-1 a good fit for everyone experiencing the syndrome?
Although there are currently no FDA-approved medications for PCOS, Ozempic and Metformin are often prescribed off-label for symptom management.
Let's explore whether these therapeutics are suitable for the 6 million individuals living with this complex syndrome.
What is PCOS?
PCOS is the most common of gynecological disorders and is also the most controversial. Prevalence has increased in the last decade, affecting 15–20% of females of reproductive age. PCOS is now also considered an endocrinological disorder due to its significant impact on metabolic processes.
PCOS is a syndrome
PCOS is a syndrome, meaning it is a collection of signs and symptoms that consistently occur together and are often linked by a common underlying cause but the exact cause may not always be fully understood.
Unlike diseases, which often have a specific and identifiable cause, syndromes are typically identified by the pattern of symptoms and may have multiple potential causes or contributing factors.
In other words, individuals with PCOS will manifest symptoms differently or similarly despite the root cause.
PCOS and insulin resistance
Potentially, females with insulin resistance can increase their risk for PCOS.
In many (but not all) females, PCOS is primarily driven by insulin resistance.
Even in lean individuals, insulin resistance can lead to hyperinsulinemia, which triggers excess androgen production. It’s also associated with chronic low-grade inflammation and an altered gut microbiome, which may result in metabolic symptoms.
How is PCOS diagnosed?
The Rotterdam Criteria is often used as a guide to help identify symptoms and make a clearer diagnosis. According to this criteria, at least two out of three main symptoms need to be present to make a legitimate claim to diagnose:
Irregular or absent ovulation (oligo/anovulation)
High levels of androgens (hyperandrogenism)
Multiple cysts on the ovaries are present on an ultrasound
Women experiencing conditions such as hypothyroidism, hyperprolactinemia, or premature ovarian failure are often misdiagnosed with PCOS.
Common comorbidities of PCOS
For nearly three decades, PCOS has been considered a lifelong condition. It is linked to a variety of health issues, including but not limited to:
Obesity
Infertility
Eating disorders
Fatty liver
Abnormal cholesterol levels
Insulin resistance
Increased risk of heart disease
Increased risk of type 2 diabetes
Hormonal imbalances
These comorbidities highlight the importance of understanding the core aspects and long-term symptom management of PCOS.
The differences between Metformin and GLP-1 agonists
Metformin and GLP-1 agonists are the frontrunners for treating type 2 diabetes.
Both are highly effective in reducing glucose serum levels and improving insulin sensitivity but operate through different mechanisms of action.
How does Metformin work?
Metformin reduces the amount of glucose production from the liver, which improves the body's response to insulin, effectively enhancing insulin sensitivity.
Unlike Ozempic, Metformin does not affect insulin secretion from the pancreas.
Some common side effects of Metformin are stomach unease, like nausea, diarrhea, gas, and bloating. To reduce side effects, doctors suggest starting with a small dose and slowly increase. Metformin can sometimes cause a deficiency in vitamin B12, especially in seniors or those taking it for a long time.
How does Ozempic work?
Ozempic (semaglutide) is classified as a GLP-1 agonist. In addition to slowing glucose production from the liver, it lowers appetite and slows digestion. Ozempic assists with managing glucose serum levels by stimulating insulin production from the pancreas.
GLP-1 is an incretin, a naturally occurring hormone produced in the gut in response to food intake. This hormone plays a key role in managing blood sugar and improving how the body uses insulin, especially in muscle and fat tissues.
Ozempic imitates this hormone by attaching to the same receptors, activating insulin secretion and glucose metabolism signaling pathways.
As a GLP-1 agonist, Ozempic helps the body in several ways:
It boosts insulin release after meals to lower blood sugar.
It reduces glucagon secretion, a hormone that raises blood sugar.
It slows down how quickly the stomach empties, making you feel full longer, which can support weight loss.
It’s important to note that weight loss with GLP-1 agonists includes drops in muscle mass. Following a protein-rich diet is essential to maintain strength and prevent musculoskeletal syndromes.
Metformin vs GLP-1 agonists for PCOS management?
It’s important to note that neither Metformin nor Ozempic are FDA-approved for PCOS. However, studies show great promise in the scope of symptom management.
You cannot effectively treat PCOS with a one-size-fits-all approach.
As a syndrome, there can be vast variation among PCOS patients, resulting in different treatment needs. To determine which would be better suited for a particular PCOS experience, it’s best to compare the mechanism and influence of each drug on the dominating aspects of PCOS.
For simplicity, let’s explore the four significant pillars of PCOS:
Metabolic Management
Hormone Imbalance
Fertility and Pregnancy
Perimenopause and Menopause
1. Metabolic management for PCOS
PCOS is closely linked to obesity and insulin resistance, with more than 50% of individuals affected being overweight or obese.
Due to the connection between obesity, insulin resistance, and increased cardiometabolic risks, addressing weight management techniques is a top priority, as successful weight loss is a strong factor in preventing metabolic comorbidities secondary to PCOS.
Insulin resistance and PCOS
In PCOS, excess insulin can stimulate the production of male hormones (androgens), leading to symptoms like acne, excessive hair growth, and irregular periods.
While insulin resistance is common in PCOS, affecting 60-70% of individuals, it’s not always used as a diagnostic factor because not everyone with PCOS experiences it.
Weight management and PCOS
PCOS is recognized as a hormonal imbalance that can trigger a harmful biological feedback loop, where insulin resistance and elevated androgen levels continually worsen each other.
Targeting insulin resistance can be key to managing PCOS. Successful weight loss strongly predicts long-term prevention of cardiometabolic disorders and hormone imbalance. Even modest weight loss (5-10% of body weight) can significantly improve reproductive health.
However, achieving weight loss in women with PCOS can be challenging, which is why many seek supplementary treatment options such as drugs like Metformin and Ozempic.
What if I have lean PCOS?
Not all women with PCOS experience weight gain or difficulty losing weight. Some women with PCOS are not overweight, and not all of them will develop metabolic syndrome. While it’s possible for a female with PCOS to be neither overweight nor have metabolic syndrome, this is less common.
It is critical to still screen for metabolic disorders such as diabetes, even if you are not experiencing weight gain. Many women with lean PCOS turn to nutraceuticals and supplementation, as included later in this article.
Metformin vs GLP-1 agonists in metabolic management of PCOS
For those experiencing metabolic symptoms of PCOS, both metformin and GLP-1 agonists stand as powerful options.
Metformin studies demonstrate significant improvements in menstrual regularity, lower androgen levels, and weight reduction in women with PCOS.
GLP-1 Agonists studies comparing GLP-1 agonists to Metformin in PCOS indicate that GLP-1 therapy improves insulin sensitivity and reduces BMI more effectively than metformin. However, results on insulin levels and testosterone reduction have been inconsistent.
GLP-1 Agonists, like Ozempic, may be more effective for the metabolic management of PCOS.
2. Hormone imbalance
One of the hallmarks of PCOS is an imbalance in sex hormones, particularly an excess of androgens, a set of sex hormones responsible for male characteristics.
These sex hormones are also present in females but in much smaller quantities and play a role in regulating functions like sexual health, mood, and metabolism.
What is steroidogenesis?
A biological process of hormone production in the ovaries in which high levels of insulin can stimulate the ovaries and adrenal glands. This results in elevated levels of steroid hormone production, especially androgens (male hormones like testosterone).
The hormone testosterone is the predominant androgen hormone, which in excess can manifest in females as:
Hirsutism: extreme hair growth on the face, chest, abdomen, and back,
Oily skin and acne: Increased androgen levels can lead to overactive sebaceous (oil) glands, contributing to acne breakouts.
Thinning hair: Elevated androgens can also cause hair thinning or hair loss on the scalp, known as androgenic alopecia.
Excess androgens can harm ovarian function, promoting “follicular arrest, altered oocyte development and maturation and anovulation.”
Metformin vs GLP-1 agonists for hormone management of PCOS
A tight association exists between weight, insulin sensitivity, PCOS hormones, and menstruation. Here are some ways Metformin and GLP-1 agonists assist with hormone balance by reducing steroidogenesis:
Metformin: It has been suggested that Metformin can reduce androgen levels through its effect on both the ovaries and adrenal glands, suppressing androgen production.
GLP-1 agonists: Drugs like Ozempic target insulin sensitivity and weight management, which can indirectly influence hormone levels.
For individuals experiencing hormone imbalance without insulin sensitivity or issues with weight management, Metformin may be a more direct solution.
3. Fertility and pregnancy with PCOS
It’s well documented by now that PCOS is marked by hormonal imbalances, which can lead to insulin resistance, a key component of metabolic syndrome.
This can lead to irregular ovulation or anovulation (the absence of ovulation), making it more challenging to conceive.
"GLP-1 reduces inflammation even before weight is lost." - Dr. Megan Lee
While there is a clear link between obesity and infertility in females with PCOS, even those who are not overweight can still face fertility challenges. These individuals may also develop metabolic syndrome despite being of normal weight, although these occurrences are less likely.
Because obesity and metabolic syndrome negatively affect fertility, it is imperative to make weight management a priority for individuals with PCOS. For instance, women with diabetes may have low levels of important reproductive hormones like estradiol, LH, and FSH, which can further complicate fertility.
Pregnancy complications and PCOS
Polycystic Ovary Syndrome (PCOS) is not only a leading cause of infertility but also increases the risk of pregnancy complications such as gestational diabetes, preeclampsia, miscarriage, etc.
Studies show that PCOS patients have a 29% increased risk of preeclampsia, the leading cause of maternal death.
Additionally, first-trimester miscarriages occur in 30-50% of PCOS patients compared to 10-15% of non-PCOS patients.
Several factors, including insulin resistance, chronic low-grade inflammation, and hormonal imbalances typical of PCOS drive the elevated risk.
Metformin vs Ozempic for fertility and pregnancy complications in PCOS
Metformin is more researched in the category of ovulation as described below:
Metformin: Early studies showed that metformin can help women with PCOS ovulate. In a group of 156 women with PCOS, 46% of those taking metformin ovulated, compared to just 24% who didn’t take it or were given a placebo.
GLP-1 agonists: There is a strong correlation suggesting that GLP-1 agonists indirectly benefit reproductive health affected by the pathogenesis of PCOS, offering a unique option to expand on treatment for PCOS.
Even though terms like "Ozempic babies" and "Ozempic baby boom" are gaining popularity, Ozempic has not been proven to directly improve fertility.
Metformin has been extensively studied for its ability to reduce pregnancy complications in women with PCOS. Studies show that it may reduce the likelihood of gestational diabetes by up to 9-fold and miscarriage rates by up to 4-fold. It may also reduce the risk of preeclampsia.
4. PCOS and menopause
Polycystic Ovary Syndrome (PCOS) can continue to affect women during the menopausal transition, presenting unique challenges due to hormonal fluctuations.
"Your postmenopausal body technically has a 'deficiency' in GLP-1 compared to your premenopausal body." - Dr. Myra Ahmed
As women transition through these stages, the loss of protective estrogen can lead to several metabolic changes, including the accumulation of visceral fat, which is associated with an increased risk of type 2 diabetes, cardiovascular disease, and metabolic syndrome.
Research indicates that women with PCOS are already at a higher risk for these conditions, and the transition into menopause can exacerbate these risks due to further hormonal imbalances.
Read more about how ozempic vs HRT can assist with menopause weight gain and body composition.
Metformin vs Ozempic for PCOS in perimenopausal or menopausal women
When considering treatment options for women with PCOS during perimenopause and menopause, both metformin and GLP-1 agonists like Ozempic offer potential benefits but target different aspects of health.
Metformin:
It continues to be effective in improving insulin sensitivity and regulating menstrual cycles.
Weight loss achieved through metformin may be less likely to negatively impact bone density and muscle mass, reducing the risk of menopausal frailty.
GLP-1 Agonists:
By reducing appetite and increasing feelings of fullness, these drugs can help combat visceral weight gain.
Loss of appetite can also influence our ability to consume powerful nutrition, which is critical during this transition.
Significant weight loss from GLP-1 agonists may raise concerns about potential negative effects on muscle mass and bone density.
Although these medications can improve insulin sensitivity, it's essential to monitor how weight loss impacts overall strength and bone health in the context of aging.
In considering treatment options, women in perimenopause and menopause can also briefly explore menopausal hormone therapy (MHT), as it can help restore hormonal balance and alleviate symptoms related to estrogen deficiency.
Unsure of your menopausal status?
As you navigate this hormonal transition, it’s crucial to understand how your body changes and how to support it effectively. To gain insights tailored to your needs, consider MenoTime, the first-ever time-to-menopause predictor.
This at-home test kit not only tells you your predicted time-to-menopause and your perimenopausal status, but it also provides personalized tips on how you can balance your hormones in advance.
Discover how MenoTime can empower you on your journey—sign up for our waitlist for updates and women’s health research!
Alternative Therapies for PCOS
For many women, especially those with lean PCOS, conventional treatments like Metformin or GLP-1 agonists did not work for them, prompting exploration into alternative therapies.
Here are some non-pharmaceutical options that individuals have had positive experiences with:
Acupuncture: Research suggests this practice may help regulate menstrual cycles, improve hormone balance, and reduce symptoms of androgen excess. Regular acupuncture sessions are believed to influence the hypothalamus-pituitary-ovarian axis.
Supplements: Several supplements may support hormonal wellbeing including probiotics, b-complex, vitamin D3, fish oil, etc.
Traditional medicine: Some individuals use adaptogenic herb, ashwagandha to reduce stress levels. Shilajit, a mineral-rich resin, is also used in Ayurveda to boost mitochondrial health and may support hormone balance.
While alternative therapies alone may not replace conventional treatments, they can complement a holistic approach to PCOS management, particularly when combined with lifestyle changes, a balanced diet, and regular exercise.
Disclaimer: This journal is not to be used as medical advice.
Comments