When Emily S., 28, was a teenager, more than one doctor told her that irregular periods were normal for her age. Dermatologists said the cystic acne along Emily’s jawline was a natural result of being 15. These explanations never convinced Emily, but the birth control pills she was prescribed did help tame her symptoms. Then when she was 22 she stopped taking them.
Three months after stopping hormonal birth control, Emily’s breakouts returned with a vengeance. Hair started to sprout just below her belly button. Her irregular periods came back; she’d go three, four months without bleeding. She was no longer a teenager. So what was the excuse now?
A Google search led Emily to information about polycystic ovary syndrome (PCOS). Even though she couldn’t check off every symptom she read about, PCOS seemed to explain a lot. She brought up her suspicions to a new doctor and received a PCOS diagnosis after a transvaginal ultrasound confirmed her ovaries had the excess follicles (sacs that hold eggs) associated with this disease.
Now, Emily wonders whether she’ll have trouble getting pregnant, as many people with PCOS do. She wonders whether there’s a link between PCOS and other health problems she experiences, like her blood sugar issues.
“That’s the thing about PCOS,” she tells SELF. “I’m like, What the hell is actually going on?”
Doctors would like to know too.
Searching for answers to questions surrounding PCOS—like what it really is, why it happens, how to diagnose it, and how to treat it—often only leads to more questions. That’s true even for PCOS experts, many of whom consider this condition to be something of a medical mystery.
Based on what we do know, PCOS is a hormonal and metabolic disorder. Its diagnostic criteria can vary, which is a complicated issue we’ll explore in a bit. In general, though, getting a PCOS diagnosis involves some combination of irregular or absent ovulation, ovaries with excess follicles (not cysts—that’s a bit of a misnomer), and high levels of androgens, or hormones that have historically been viewed as “male,” like testosterone. These issues can present as symptoms like irregular periods, acne, excess face and body hair, scalp hair loss, and weight gain, according to the Centers for Disease Control and Prevention (CDC). Per the CDC, the disorder affects an estimated 6 to 12 percent of women of reproductive age, which translates to about 5 million people dealing with this confusing condition.
The good news is that experts aren’t giving up on figuring out PCOS. Here, SELF explores the current state of PCOS knowledge and where experts believe research on the condition is headed.
What causes PCOS?
There isn’t one definitive cause of PCOS, but researchers know of several suspected factors that might play off each other. It’s possible that PCOS is always caused by some combination of these factors, but pinpointing the exact triggers in one person is a little ambitious, even for experts, Richard Legro, M.D., chair of the Department of Obstetrics and Gynecology at Penn State, tells SELF.
Excess insulin brought on by insulin resistance is thought to be a significant factor. This gets pretty complicated, but bear with us. Your cells need the hormone insulin to absorb glucose (sugar from food) for energy, according to the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). But if you have insulin resistance, your cells don’t absorb glucose like they should. This can confuse your body into thinking you just need more insulin to compensate and be able to absorb glucose normally, so your pancreas might churn out higher levels of this hormone. Long story short, doctors believe this excess insulin due to insulin resistance might make your ovaries produce extra androgens, like testosterone. (Insulin resistance can also lead to pre-diabetes and type 2 diabetes over time.)
Some of the most familiar markers of PCOS (think acne, excess face and body hair, scalp hair loss, and irregular or absent ovulation) can happen as the result of extra androgens, though it’s not clear if the excess androgens are an actual cause of PCOS or just a symptom of another potential cause (like excess insulin from insulin resistance). It’s probably pretty easy for you to see how extra testosterone could translate into something like more face and body hair, but you might find it harder to pin down how this would relate to irregular ovulation. Well, you’re in great company, because doctors aren’t too sure either.
One possible explanation for how androgens mess with ovulation is that these hormones build up inside ovarian follicles, keeping the follicles from maturing and releasing eggs, which can lead to the excess follicles seen on an ultrasound like Emily’s.
But elevated androgen levels aren’t always a sign of PCOS. This can also happen with other health conditions like Cushing’s syndrome or congenital adrenal hyperplasia, so doctors will try to rule out other health conditions before they assume that excess androgen points to PCOS.
Another possibility is that PCOS might happen, at least in part, when the brain’s hypothalamus sends incorrect hormone signals from the pituitary gland (a pea-sized organ that produces hormones) to the ovaries, Leanne Redman, Ph.D., director of the Reproductive Endocrinology and Women’s Health Research Program at Pennington Biomedical Research Center in Baton Rouge, tells SELF. Here’s how that might work: The pituitary gland regulates levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which then prepare ovarian follicles for maturation. If these hormones are thrown off, it can prevent you from ovulating, which can lead to irregular periods—a classic sign of PCOS.
Again, this could be a cause of PCOS or it could be a symptom of another cause, since some evidence suggests that insulin resistance can influence how the pituitary gland regulates LH and FSH (though the data is too inconsistent to definitely cite it as cause and effect, according to 2012 research on insulin resistance and PCOS in Endocrine Reviews).
Genetics could also be a factor in PCOS development. PCOS tends to cluster in families, which some experts believe may point to a strong genetic link, Redman says. Whether someone develops PCOS could be the result of a genetic variation (i.e., how a DNA sequence varies in each individual’s genetic material).
Researchers have begun to unravel the genetic origins of this disorder through DNA samples. A 2019 meta-analysis of 261 people in The Journal of Clinical Endocrinology & Metabolism revealed that a gene called DENND1A could have a role in the development of PCOS in white families of European heritage.
“This may not apply to women of other races and ethnicities, but…it’s really the first gene that seems to play a major role in PCOS development and it strongly suggests—at least in the women and families that have these rare genetic variants—that altered androgen production is a key abnormality causing PCOS,” Andrea Dunaif, M.D., the chair of endocrinology at Mount Sinai School of Medicine and one of the study authors, tells SELF. Various research groups are also hoping to investigate the role of genes in PCOS in black and Chinese people to see what kind of connection may exist there, Dr. Dunaif says.
Additionally, some experts believe fetuses that are exposed to unusually high testosterone levels while in the womb (like if the pregnant person has PCOS or diabetes) may be more inclined to develop this disorder, Redman says. The excess testosterone could influence the genetic material of the fetus, including any eventual eggs and ovaries it develops. This seems to set up these individuals for developing PCOS later on, though some research suggests the deciding factor could be the environment they grow up in, Redman says. For example, not having access to nutritious foods and being inactive could mean developing insulin resistance that could further predispose someone in this situation to PCOS, she explains.
What PCOS diagnosis and treatment look like
Now that you know more about the complicated tangle of potential PCOS causes, you probably won’t be surprised to find out that diagnosis can be similarly tricky.
There are actually multiple versions of PCOS diagnostic criteria out there. Overall, doctors tend to look for at least two of these symptoms to diagnose PCOS: irregular or absent ovulation (as evidenced by irregular or absent periods), evidence or suggestion of ovaries with excess follicles (like via ultrasound), and symptoms of high levels of androgens (like excess face and body hair, weight gain, and hormonal acne).
But the specific mix of symptoms doctors are looking for depends on the exact diagnostic criteria they’re using. For instance, in 1990 the National Institutes of Health (NIH) created PCOS diagnostic criteria that required signs of hyperandrogenism and absent or irregular ovulation, but the excess ovarian follicles were optional. (Not everyone with PCOS even has these extra follicles and some people without PCOS have them, the CDC explains.) In 2003, a consensus workshop in Rotterdam, Netherlands, released their own criteria saying that any two out of those three potential signs of PCOS should be required for diagnosis. Finally, in 2009 the Androgen Excess and PCOS Society said someone would need to exhibit hyperandrogenism plus either of the other possible signs to be diagnosed with PCOS.
Confused yet? It’s no wonder why people like Emily often see multiple doctors before receiving a PCOS diagnosis.
Because the consensus among experts is that PCOS has no cure, researchers focus on treatment. If your doctor thinks you have PCOS, they may recommend hormonal birth control to regulate your hormone levels and menstrual cycle, according to the Mayo Clinic. They may also prescribe drugs like metformin to help your body become more sensitive to insulin, spironolactone for skin issues like acne brought on by androgen excess, or medications to stimulate ovulation if you’re having trouble getting pregnant.
While the FDA has approved medications to treat the symptoms of PCOS, it has yet to approve a drug specifically for the disorder. Many people with PCOS have to mix and match drugs to find relief. Emily, for example, decided to go back on hormonal birth control and added spironolactone to help with her symptoms.
Redman believes more and more research will focus on prevention in at-risk girls, like those who are insulin-resistant or whose mothers or sisters have PCOS. Doctors could, for example, test babies for any potential PCOS-related genes, then test whether certain diets prevent children with those genes from developing issues like insulin resistance that can lead to excess insulin production, Redman says. (Diet has been shown to help reduce PCOS symptoms in some people. You can read all about that here.)
“The future needs to be on prevention,” Redman says. “I think with more prevention in younger girls we can also improve the dialogue and the conversation about symptoms so that we can tackle them earlier.”
The challenges of researching PCOS
So why don’t we know enough about this disorder? Recruiting participants and keeping them enrolled is one major challenge in investigating PCOS, Redman says. Researchers typically want to recruit more patients than necessary since some people drop out of studies, she says, and this can be tough to do.
For patients with PCOS, the major benefits of participating in research could include free testing, evaluations, and recommendations that would otherwise cost them. It’s not just about the personal payoff, though. “My experience over more than 30 years has been that women with PCOS are very interested in helping us better understand their problem,” Dr. Dunaif says. “They’ve been so frustrated with their own cases that they want to help out.”
But participating in PCOS studies often requires that patients stop other medications, including hormonal birth control and insulin-sensitizing drugs, Redman says. She speculates that people do not want to give up medications that manage their symptoms for an unknown result, which can lead to less than ideal sign-up numbers.
Then there’s the process of actually participating in the studies. In general, the more prolonged studies are, the higher the dropout rates are, Dr. Dunaif adds.
“The highest dropout rates in these studies are usually in your control group, your normal subjects. They really have no incentive other than getting compensated for time and effort, and we don’t compensate them enough just on that basis,” Dr. Dunaif says. Controls can generally earn between $5 to $25 for one blood sample to hundreds of dollars for studies that last eight hours or so and require intravenous procedures, she tells SELF.
Dr. Dunaif has found that getting participants on board with gene-sequencing research has been easier because it usually involves getting their blood drawn once without the need for follow-up visits. “We really have to be very pragmatic when designing studies with human participants to not make it a burden,” she says.
A lack of financial backing is another huge barrier in PCOS research. The NIH is the largest public supporter of biomedical research in the world, according to the World Health Organization (WHO). Looking at how much of that funding goes to PCOS paints a pretty telling picture.
A 2017 study in The Journal of Clinical Endocrinology & Metabolism used the NIH Research Portfolio Online Reporting tool to look at how many grants the organization awarded to PCOS, rheumatoid arthritis, lupus, and tuberculosis between 2006 and 2015. Those last three illnesses affect about as many people in the U.S. as PCOS (or fewer) and appear to have a similarly negative impact on quality of life, according to past research. The study found that the NIH awarded less funding to PCOS ($215.12 million) than to these other conditions ($454.39 million for rheumatoid arthritis, $773.77 million for tuberculosis, and $609.52 million for lupus). The study authors concluded that “PCOS research may be underfunded considering its prevalence, economic burden, metabolic morbidity, and negative impact on quality of life.”
There are a few reasons why this may be the case.
“Most of the studies, most of the researchers, and most of the administrators tend to be [men] who are not necessarily interested in women’s health,” Ricardo Azziz, M.D., M.P.H., M.B.A., chief officer of academic health and hospital affairs at the State University of New York and lead study author of the NIH grant report, tells SELF. “The reality is that while some disorders of women have received a lot of attention, like breast cancer, others have not.”
Funding agencies prioritize disorders that have the greatest public health impact, such as the highest death rates, Dr. Dunaif says. This helps explain why conditions like heart disease and breast cancer (which kill around 300,000 and 41,000 women each year, respectively) have so much research behind them.
The confusion about the causes of PCOS may also make it a bit easier to fall through the research cracks. Institutes within the NIH tend to consider PCOS a reproductive disorder rather than a reproductive and metabolic disorder, Dr. Azziz says. So most of the funding (about 68 percent) that goes toward PCOS research comes from the National Institute of Child Health and Human Development (NICHD), which focuses on reproductive issues. Limiting PCOS to being viewed as just a reproductive disorder means researchers who are interested in metabolic aspects of PCOS, like its link to diabetes and nutrition, can have trouble securing funding, Dr. Azziz says. That doesn’t mean this doesn’t happen, but it’s less common.
The lack of funding for PCOS research also discourages some young scientists from entering this field, Dr. Dunaif says. On top of student-loan debt hanging over new graduates’ heads, a dearth of research money can steer potential scientists away from taking a chance on grant writing, she explains.
In addition to all of that, sometimes good researchers end up leaving the field, Dr. Azziz says. His own data shows that the number of PCOS research grant applications dropped 42 percent from 2006 to 2015, much more than any of the other conditions studied. With fewer competitive researchers come fewer breakthrough studies, Dr. Azziz explains.
What really needs to happen next
We need groundbreaking research on how to better diagnose PCOS, better treat it, and better understand its causes so that experts may be able to help prevent it.
One proposed solution to expand the PCOS funding pool is a name change to be more all-encompassing. (This would also nod to the fact that not everyone with this condition has excess ovarian follicles and people with excess ovarian follicles don’t always have this condition.) Experts haven’t agreed upon a new name yet. As Dr. Azziz describes in a fascinating 2014 paper in The Journal of Clinical Endocrinology & Metabolism, potential options might include “metabolic hyperandrogenic syndrome,” “polycystic ovary-hyperandrogenic syndrome,” and “polycystic ovary-anovulatory syndrome,” which would each correspond to different mixes of symptoms this condition most commonly causes.
As Dr. Azziz notes in the paper, the final consensus from an earlier NIH meeting about PCOS said, “The right name will enhance recognition of this major public health issue for women, educational outreach, ‘branding,’ and public relations and will assist in expanding research support.” Ideally it could have a domino effect that would address many of the research-related barriers in learning more about PCOS.
On-the-ground advocates are helping to push for this much-needed research as well.
Sasha Ottey founded PCOS Challenge in 2009 with the goal of mobilizing PCOS advocates to reach out to their representatives on behalf of people with the disorder. Congressional action can lead to more awareness and research funding, Dr. Azziz says. “PCOS Challenge has been doing a tremendous amount of work trying to move awareness forward,” he adds.
Ottey and her team found that other conditions had earned spots on the calendar of National Health Observances. So, the organization decided that PCOS needed an awareness month. PCOS Challenge formed a caucus to scout out members of Congress who were willing to work with the organization as its advocates on Capitol Hill, Ottey says.
Fast forward to December 2017, and the U.S. Senate passed a resolution introduced by Senator Elizabeth Warren to acknowledge “the seriousness of” PCOS, dubbing September 2018 as the first official PCOS Awareness Month. In February 2019, the U.S. House introduced its resolution to make September 2019 the second official PCOS Awareness Month. (These resolutions are generally introduced and passed every year, even for observances that are more established, like American Heart Month in February.)
“We’re taking back control by sharing our stories,” Ottey tells SELF. “Patients with PCOS, physicians, and researchers are now feeling more empowered because there is a sort of pipeline to get to an end result: more financial resources for PCOS research, awareness campaigns, and other initiatives to educate patients and health care providers.”
That’s what so much of this quest to demystify PCOS comes down to: the need for validating, illuminating, and potentially life-changing knowledge about this disease. “When I was diagnosed, I was more relieved than anything,” Emily says. “Why would you subject yourself to being uncomfortable or in pain or internally struggling with whether or not something’s wrong with your body? I would just rather know.”
Having diabetes can affect your menstrual cycle. Conversely, a menstrual period can impact daily diabetes management. Get a primer on the many ways diabetes and menstrual periods are connected, with tips on everything from managing irregular periods to optimizing blood sugars during menstruation.
Just like maintaining normal blood glucose levels, menstrual cycles are the result of an intricate series of hormone signals, said Dr. Emily Jungheim, a board member of the Society for Reproductive Endocrinology and Infertility and a professor of obstetrics and gynecology at Northwestern University Feinberg School of Medicine. “People with diabetes are at higher risk for having irregular or unpredictable menstrual cycles, and in medicine we refer to the menstrual cycle as ‘the fifth vital sign,’ after blood pressure, heart rate, respiration rate and temperature.” If you are not having regular monthly cycles, or if your monthly cycles are changing significantly from what is normal for your body—either because they are more frequent or less so—seek advice from your healthcare team.
As a refresher, the menstrual cycle is a monthly hormonal process that ensures a woman can get pregnant. It is counted from the first day of your period, which occurs over several days when blood and tissue lining the uterus sheds and flows out of the vagina. After the period ends, hormone levels of estrogen and progesterone fluctuate. During the menstrual cycle, the body prepares to release an egg in a process called ovulation. This egg can then be fertilized by sperm to create an embryo, which ultimately grows into a fetus, and later, a baby.
For most women—with or without diabetes—monthly periods occur every 21 to 35 days, and last from two to seven days, according to the Mayo Clinic. With that being said, each woman’s period is different, and cycles can be inconsistent at times, especially following a woman’s first period and as she approaches menopause.
Irregular Menstrual Cycles and Diabetes
Anovulation
“Women with diabetes are at higher risk for menstrual abnormalities due to what is called anovulation,”said Jungheim.
Anovulation is when ovulation, a normal part of the menstrual cycle where the ovary releases an egg into the Fallopian tube, does not occur. “This is really important, as ovulation is required for pregnancy. When women aren’t ovulating regularly and predictably, it can make it harder to get pregnant,” Jungheim adds. In addition, if you don’t have a period then you won’t know when you are more fertile, or more likely to conceive when having sex.
Since the menstrual cycle is what determines when a woman is fertile and when she is not, problems with your period indicate the cycle isn’t progressing the way it is supposed to. The important thing is to actually have a monthly period, Dr. Jungheim said.
For women who are within the age range for childbearing, it’s normal to get a period every month from the onset of their first period until menopause. Pay attention to certain things, such as different forms of birth control, pregnancy, breastfeeding, weight gain or loss, different health conditions, and menopause/perimenopause, which can cause the body to stop ovulating, and therefore, not have a period.
“If someone with diabetes notices that she is experiencing vaginal bleeding more often than every month, or less often than every month, she should see her healthcare professional for further investigation,” Jungheim said. Know, however, that women can sometimes have periods that are more or less frequent than what is considered the average experience. Learn what is normal for you, and be aware of period changes that aren’t typical for you.
If you’re experiencing anovulation (no ovulation, so no period), there can be many causes, both diabetes-related and not.“That’s where a visit to a good ob-gyn or a reproductive endocrinologist is imperative so that these factors can be considered, appropriate diagnostic tests ordered, and an individualized plan can be developed,” Jungheim added. “How diabetes impacts or changes these factors is very specific to the individual.”
Polycystic Ovarian Syndrome (PCOS)
Women with type 2 diabetes have higher rates of obesity, which is often associated with polycystic ovarian syndrome, said Veronica Brady, an assistant professor at the University of Texas Cizik School of Nursing and a spokesperson for the Association of Diabetes Care & Education Specialists (ADCES). The most common symptom of polycystic ovarian syndrome is irregular periods. “Sometimes women [with type 2 diabetes] may experience issues with conception, which could be due to irregular periods,” Brady said.
Being Underweight
Women with type 1 diabetes who are underweight may experience irregular periods as well, as a normal body weight is needed to maintain the menstrual cycle and support pregnancy, Brady added.
Regardless of the reason, if you are having irregular periods—which Brady defines as not having a period for more than three months and you are not pregnant or in perimenopause or menopause—talk to your healthcare professional. Periods that are heavy (those which last for five to seven days with large clots, or instances of bleeding a couple times a month) should also be discussed with a healthcare professional, she said.
How a Menstrual Period Can Affect Blood Sugars
Added Cravings and Other Premenstrual Symptoms
When your period arrives, it is possible that it can cause your blood sugars to soar or your body to crave certain foods.
Some women experience premenstrual symptoms, a week or two before the period begins, that can cause cravings for certain foods and may impact mood, while others do not.
Higher—or Lower—Glucose Levels Than Usual
“In my practice, as well as in the literature, it has been noted that prior to starting their cycle, many women report that their blood glucose levels run higher,” said Brady. Women using insulin pumps may have to increase their basal rates two to three days before their period starts, to cover higher blood sugars. “I usually advise women who are on insulin therapy and notice an increase in blood glucose readings to increase their basal (long-acting) insulin by 10 to 20 percent (depending on how high their blood glucose readings are) for two to three days prior to their menstrual period, and to maintain the higher dose throughout their period,” she said.
Some women with type 1 diabetes may also notice that, at the start of their period, their blood glucose is lower. They may need to decrease their basal insulin for the first one to two days, and then they may need more insulin for the next three to five days, Brady added.
“If someone is having difficulty maintaining stable blood sugar levels, they should keep a menstrual diary and match it up with their blood sugar data,” Brady said. You can use an app or use a pen and paper to note trends and match them to where you are in your menstrual cycle. If you aren’t having periods at predictable intervals after three months of tracking, or your periods occur more often than every 24 days or so, reach out to a healthcare professional.
“If someone notes an association [between blood sugar levels and their menstrual cycle], she may want to talk to her healthcare professional about options for controlling the hormonal shifts that occur with menstrual cycles,” said Jungheim.
Managing Period Discomfort With Diabetes
Once a period arrives, it can cause abdominal pain or cramps, heavy bleeding, or migraines. Over the counter pain relievers and warm compresses to the abdomen can help soothe cramping and abdominal discomfort. But in terms of specific advice for women with diabetes, “the primary thing to consider is to manage your blood glucose as much as possible,” Brady said.
“There are lots of [treatment] options that are available” to help with period problems, said Jungheim. “Sometimes it can be trial and error to find the right answer, but often if we are persistent we can find a solution that works for the individual.”
Polycystic ovary syndrome is characterised by excessive levels of androgens and ovulatory dysfunction, and is a common endocrine disorder in women of reproductive age. Polycystic ovary syndrome arises as a result of polygenic susceptibility in combination with environmental influences that might include epigenetic alterations and in utero programming. In addition to the well recognised clinical manifestations of hyperandrogenism and ovulatory dysfunction, women with polycystic ovary syndrome have an increased risk of adverse mental health outcomes, pregnancy complications, and cardiometabolic disease. Unlicensed treatments have limited efficacy, mostly because drug development has been hampered by an incomplete understanding of the underlying pathophysiological processes. Advances in genetics, metabolomics, and adipocyte biology have improved our understanding of key changes in neuroendocrine, enteroendocrine, and steroidogenic pathways, including increased gonadotrophin releasing hormone pulsatility, androgen excess, insulin resistance, and changes in the gut microbiome. Many patients with polycystic ovary syndrome have high levels of 11-oxygenated androgens, with high androgenic potency, that might mediate metabolic risk. These advances have prompted the development of new treatments, including those that target the neurokinin-kisspeptin axis upstream of gonadotrophin releasing hormone, with the potential to lessen adverse clinical sequelae and improve patient outcomes.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Polycystic ovary syndrome is a common metabolic and reproductive disorder characterised variably by high levels of androgens, insulin resistance, and ovulatory dysfunction, with not all patients affected by these three parameters. These changes manifest as hyperandrogenism (hirsutism, acne, or scalp hair loss, or a combination of these), oligomenorrhoea or amenorrhoea, and morphological features of polycystic ovaries on ultrasound. Long recognised as a reproductive disorder, polycystic ovary syndrome is now also established as a metabolic condition associated with long term health risks, including type 2 diabetes and cardiovascular disease.1 Adverse mental health outcomes and reduced quality of life have also been reported.1 Polycystic ovary syndrome is therefore associated with substantial healthcare costs and resource utilisation. International surveys report a high level of dissatisfaction with care,2 not least because current treatments are often only modestly effective in alleviating symptoms and minimising long term risks. International guidelines recognise the low quality of evidence and the critical need for better research.3
An improved understanding of the pathogenesis of the disease might result in the development of new treatments and better patient outcomes. Recent studies have advanced our understanding of these pathophysiological processes. Neuroendocrine dysregulation leads to abnormal high frequency pulsatile secretion of gonadotrophin releasing hormone, and hypothalamic kisspeptin, neurokinin B, and dynorphin A neurons (so-called KNDy neurons) are integral regulators of this process.4 Although increased production of ovarian and adrenal androgens contribute to hyperandrogenism, peripherally generated 11-oxygenated androgens are emerging as important predictors of metabolic risk.5 6 Together with advances in our understanding of adipocyte biology, insulin resistance, the gut microbiome, and insights from genome-wide association studies, these studies could improve our understanding of the pathogenesis of this disease. New treatments based on these observations are now in various stages of preclinical or clinical development.
This review outlines our current understanding of the key pathophysiological processes in polycystic ovary syndrome. We discuss the significance of new research into neuroendocrine dysfunction, disrupted steroidogenesis, and changes in adipocyte biology, and the potential implications for the diagnosis and management of polycystic ovary syndrome. Finally, we consider the benefits and limitations of current drug treatments, along with a review of the evidence for emerging drug treatments.
Epidemiology
Polycystic ovary syndrome is a common endocrine disorder in women of reproductive age,7 with a prevalence of 4-21% depending on the diagnostic criteria used.8 A systematic review of 13 studies found a slightly higher estimate of the prevalence in black and Middle-Eastern than in Chinese and white populations,9 although inconsistencies in diagnostic criteria and recruitment methods make comparisons between ethnic groups challenging.10 The global disease burden seems to be increasing at a high rate. In 2019, an age standardised point prevalence of 1677.8 per 100 000 and an annual incidence of 59.8 per 100 000 population were reported based on data from 204 countries, representing increases of 30.4% and 29.5%, respectively, since 1990.11 The rising incidence, and accompanying morbidity,11 emphasises the importance of recognising polycystic ovary syndrome as an international public health priority.
Sources and selection criteria
We searched PubMed, Medline, and Embase from 1 January 2010 to 28 February 2023 for articles in the English language, with the search terms: “polycystic ovary syndrome,” “polycystic ovarian syndrome,” “PCOS,” “aetiology,” “etiology,” “cause,” “pathogenesis,” and “pathophysiology.” We excluded articles on endocrine conditions that might lead to secondary polycystic ovary syndrome, including acromegaly, androgen secreting tumours, congenital adrenal hyperplasia, and Cushing’s syndrome. To identify registered clinical trials, we searched ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials (CENTRAL), and the International Standard Randomised Controlled Trial Number (ISRCTN) registry with the search terms “PCOS,” “polycystic ovary syndrome,” and “polycystic ovarian syndrome.” We prioritised large scale, randomised controlled trials and systematic reviews. We also included relevant articles identified from reference lists of retrieved articles.
Pathogenesis
Neuroendocrine disruption
Polycystic ovary syndrome is characterised by increased pulse frequency of gonadotrophin releasing hormone and reduced negative feedback from sex steroids at the level of the hypothalamus.4 12 Gonadotrophin releasing hormone is released from neurons in the hypothalamic infundibular nucleus in a pulsatile manner, resulting in increased secretion of luteinising hormone and follicle stimulating hormone. The pulse frequency of gonadotrophin releasing hormone is controlled by multiple upstream endocrine and neural factors, with a higher frequency favouring secretion of luteinising hormone and a lower frequency favouring secretion of follicle stimulating hormone. In women with polycystic ovary syndrome, raised levels of luteinising hormone cause excess production of ovarian thecal androgens, whereas relative deficiency of follicle stimulating hormone causes follicular arrest, polycystic ovarian morphology, and oligo-ovulation.4 The reduction in sex steroid feedback on release of gonadotrophin releasing hormone is thought to occur upstream of the hormone itself because gonadotrophin releasing hormone neurons do not have receptors for oestrogens or progesterone13 (figure 1). KNDy neurons have an important role in this regard (figure 1).
Kisspeptins are a family of peptides encoded by the KISS1 gene which act on the neuronal G protein coupled receptor KISS1R. KISS1 encodes prepro-kisspeptin, which is cleaved to produce the biologically active peptides KP54, KP14, KP13, and KP10.14 Two discrete neuronal populations exist: KNDy neurons in the infundibular nucleus function as the gonadotrophin releasing hormone pulse generator15 and mediate negative feedback from oestradiol,16 whereas a separate kisspeptin population located in the preoptic area mediates oestradiol positive feedback to produce the mid-cycle surge in luteinising hormone.16 17 Kisspeptin neurons express sex steroid receptors (progesterone and oestrogen receptors) required for negative feedback on gonadotrophin releasing hormone pulsatility.17 18KISS1 is also expressed in adipose tissue where it is regulated independently of hypothalamic KISS1.19 Circulating levels of kisspeptin are higher in patients with polycystic ovary syndrome than in controls20 and although the origin of this excess is not entirely clear, a raised pulse frequency of kisspeptin in women with oligomenorrhoea and polycystic ovary syndrome suggests a hypothalamic source.21 Moreover, physiological coupling of kisspeptin and luteinising hormone pulsatility is lost in these women.21 The exact mechanisms for these effects are unclear, with inconsistent data from preclinical models on the existence and direction of dysregulated gonadotrophin releasing hormone pulsatility mediated by kisspeptin.22
Pathophysiology and neuroendocrine disruption of the hypothalamo-pituitary-gonadal axis in polycystic ovary syndrome. (Left) Increased pulsatility of gonadotrophin releasing hormone (GnRH) causes increased secretion of luteinising hormone, consequent disrupted folliculogenesis, and increased production of ovarian androgens. Adrenal androgens are also increased, including 11-oxygenated androgens which are activated peripherally by renal 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) and aldo-keto reductase 1C3 (AKR1C3) in adipocytes. Steroid-5α-reductase (SRD5A) converts 11-ketotestosterone to 11-ketodihydrotestosterone. Excess levels of androgens stimulate deposition of abdominal adipose tissue which subsequently increases insulin resistance and hyperinsulinism. Hyperinsulinism stimulates AKR1C3 activity, increases androgen production from the ovaries (by its action as a co-gonadotrophin) and adrenal cortex, reduces production of hepatic sex hormone binding globulin, and inhibits progesterone mediated negative feedback onto GnRH neurons, worsening androgen excess in a vicious cycle. (Right) Kisspeptin, neurokinin B, and dynorphin A neurons (KNDy neurons) act in a paracrine and autocrine way to regulate release of kisspeptin onto GnRH neurons and consequent GnRH pulsatility. Neurokinin B binds to neurokinin 3 receptors (NK3R) to stimulate release of kisspeptin whereas dynorphin binds to kappa opioid receptors to inhibit kisspeptin release. γ-aminobutyric acid (GABA) and anti-müllerian hormone (AMH) bind to GABAA receptors (GABAAR) and AMH receptor type 2 (AMHR2), respectively, to stimulate GnRH pulsatility. Impaired negative feedback from oestradiol and progesterone is seen at the level of the hypothalamus. Neuroendocrine abnormalities in the control of these components are shown in red. OR=oestrogen receptor; PR=progesterone receptor
Neurokinin B and dynorphin are expressed by KNDy neurons and act in an autocrine and paracrine way to control release of kisspeptin (figure 1). Neurokinin B preferentially binds to the neurokinin 3 receptor (encoded by TACR3) to stimulate gonadotrophin releasing hormone pulsatility.4 23 Unlike KISS1 null mice, mice deficient in components of neurokinin B signalling can still generate surges in luteinising hormone and conceive, suggesting that compensatory pathways exist which contribute to the generation of kisspeptin and gonadotrophin releasing hormone pulses.17 24 25 This milder effect of neurokinin B blockade might avoid excessive reduction in gonadotrophin releasing hormone pulsatility, making it an attractive target for treatment.4 Dynorphin, which activates kappa opioid receptors on KNDy neurons to inhibit secretion of gonadotrophin releasing hormone,22 26 has been shown to mediate progesterone negative feedback on gonadotrophin releasing hormone neurons in sheep27 and humans.22 28
Neuronal activity of gonadotrophin releasing hormone is also regulated by other substances, including γ-aminobutyric acid (GABA) and anti-müllerian hormone, both of which stimulate gonadotrophin releasing hormone neurons directly. GABA exerts an excitatory effect on gonadotrophin releasing hormone neurons through GABAA receptors, and GABA levels in cerebrospinal fluid can be raised in patients with polycystic ovary syndrome.29 Anti-müllerian hormone is secreted by ovarian granulosa cells, where raised levels in women with polycystic ovary syndrome disrupt folliculogenesis and ovulation.30 Anti-müllerian hormone might also have neuroendocrine effects: 50% of gonadotrophin releasing hormone neurons in mice and humans express anti-müllerian hormone receptor type 2,31 with studies implicating anti-müllerian hormone in neuronal migration of gonadotrophin releasing hormone,32 gonadotrophin releasing hormone pulsatility, and secretion of luteinising hormone.30
Classical pathway of androgen synthesis
High levels of androgens is a primary defect in polycystic ovary syndrome. Cholesterol is converted to androgens by a cascade of enzymes common to all steroid producing organs, with tissue specific variations resulting in different steroid hormone profiles.33 In polycystic ovary syndrome, increased production of ovarian androgens by the classical pathway is driven by increased secretion of pituitary luteinising hormone, the action of insulin as a co-gonadotrophin, and increased thecal cell hypersensitivity to luteinising hormone.34–36Figure 2 summarises the classical pathway of steroidogenesis. Through a sequence of reactions, cholesterol is converted to dehydroepiandrosterone, which is then converted to androstenedione by 3β-hydroxysteroid dehydrogenase type II and subsequently to testosterone by aldo-keto reductase type 1C3 (AKR1C3).35
Classical pathway of androgen synthesis. Luteinising hormone stimulates the classical pathway of androgen synthesis in ovarian theca cells. Cholesterol is transported to the inner mitochrondrial membrane by steroidogenic acute regulatory protein (StAR). A cleavage system of the cytochrome P450 enzyme, CYP11A1, ferrodoxin, and ferrodoxin reductase converts cholesterol to pregnenolone. Expression of CYP11A1 is stimulated by activation of the luteinising hormone receptor. Pregnenolone is transported to smooth endoplasmic reticulum where it is converted to 17-hydroxypregnenolone and subsequently to dehydroepiandrosterone by the 17-hydroxylase and 17,20-lyase subunit of the CYP17A1 enzyme, respectively. Dehydroepiandrosterone is then converted to androstenedione or androstenediol and subsequently to testosterone by a combination of 3β-hydroxysteroid dehydrogenase type II (HSD3B2) and aldo-keto reductase type 1C3 (AKR1C3). 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) also catalyses the conversion of dehydroepiandrosterone to androstenediol. HSD3B2 converts pregnenolone and 17-hydroxypregnenolone to progesterone and 17-hydroxyprogesterone, respectively, which are substrates for a back door alternative pathway of androgen synthesis. Androstenedione and testosterone diffuse into granulosa cells where they are converted to oestrogens by the action of aromatase (CYP19A1), under the control of follicle stimulating hormone receptor activation. Testosterone can be converted to dihydrotestosterone by steroid 5α-reductase (SRD5A) in peripheral tissues
Increased activity of ovarian 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone to active cortisol, might also have a role in the pathogenesis of polycystic ovary syndrome.37 Overexpression of ovarian 11β-HSD1 in rats caused polycystic ovarian morphology, oestrous cycle, and reproductive hormone abnormalities.37 Although 11β-HSD1 is widely expressed, dysregulation seems to be tissue specific, because hepatic 11β-HSD1 activity is impaired and expression of 11β-HSD1 in subcutaneous adipose tissue is increased in patients with polycystic ovary syndrome.38 Raised circulating levels and ovarian expression of vascular endothelial growth factor also contribute to the hypervascular, hyperplastic appearance of the ovarian stroma and theca interna in polycystic ovary syndrome, and might contribute to increased ovarian androgen synthesis.39
Androgen synthesis in adrenal glands and peripheral tissues
Polycystic ovary syndrome was previously thought to be primarily a disease of excess production of androgens in the ovaries, but the adrenal glands and peripheral tissues are now considered important sources of androgens in patients with polycystic ovary syndrome. Increased concentrations of dehydroepiandrosterone sulphate, an almost exclusive product of the adrenal cortex,40 are apparent in 20-30% of patients with polycystic ovary syndrome.41 This finding seems to be the result of increased secretory activity of the adrenal cortex because no change in pituitary responsiveness to corticotrophin releasing hormone or reduction in the minimal stimulatory dose of adrenocorticotropic hormone required for adrenal hormone production is seen.42 Changes in steroidogenesis, such as increased enzymatic activity of the 17-hydroxylase subunit of the cytochrome P450 enzyme, CYP17A1, might account for this hyper-responsiveness.43
Other adrenal androgens are also secreted in excess, including 11β-hydroxyandrostenedione and 11β-hydroxytestosterone.5 44 The adrenal androgen 11β-hydroxyandrostenedione is abundant and was previously thought to have little physiological importance because of its weak androgenic activity. Recent studies, however, have shown that 11β-hydroxyandrostenedione can be metabolised to 11-ketotestosterone and 11-ketodihydrotestosterone, termed 11-oxygenated androgens, because of the presence of an oxygen atom on carbon 11.45 Both 11-ketotestosterone and 11-ketodihydrotestosterone bind to androgen receptors with similar affinity and potency to testosterone and dihydrotestosterone.46 47 Mass spectrometry analyses have shown that 11-oxygenated androgens are the dominant circulating androgens in women with polycystic ovary syndrome and correlate substantially with markers of metabolic risk.5 The synthesis of 11-oxygenated androgens is reliant on the peripheral activation of adrenal derived androgens (figure 3). 11β-hydroxysteroid dehydrogenase type 2 is an enzyme expressed by the kidney that converts 11β-hydroxyandrostenedione to 11-ketoandrostenedione, and 11β-hydroxytestosterone to 11-ketotestosterone.45 Adipose tissue also has enzymes responsible for potent androgen formation, however, and might represent the dominant source of circulating 11-oxygenated androgens.45 48
Expression of the androgen activating enzyme, AKR1C3, in subcutaneous adipose tissue is increased in women with polycystic ovary syndrome compared with matched controls.6 49 Thus concentrations of androgens in adipose tissue are increased in women with polycystic ovary syndrome, accompanied by inhibition of lipolysis and increased de novo lipogenesis.6 These observations suggest that inhibition of AKR1C3 might be an attractive therapeutic target in patients with polycystic ovary syndrome.
Pathway for 11-oxygenated androgen synthesis, which begins in the adrenal cortex. Androstenedione and testosterone are produced by the classical pathway (figure 2). Dehydroepiandrosterone is diverted to downstream androgens or sulphonated to dehydroepiandrosterone sulphate by the sulphotransferase, SULT2A1. Androstenedione and testosterone are hydroxylated by 11β-hydroxylase (CYP11B) to produce abundant 11β-hydroxyandrostenedione (11OHA4) and smaller amounts of 11β-hydroxytestosterone (11OHT). Renal 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) converts 11OHT to 11-ketotestosterone (11KT) and 11OHA4 to 11-ketoandrostenedione (11KA4). In adipose tissue, 11KA4 is metabolised to 11KT and 11-ketodihydrotestosterone (11DHKT) by aldo-keto reductase type 1C3 (AKR1C3) and steroid-5α-reductase (SRD5A), respectively. 11OHA4 is metabolised to 11OHT and 11β-hydroxydihydrotestosterone (11OHDHT) by 17β-hydroxysteroid dehydrogenase 2 (HSD17B2) and SRD5A, respectively. 11KT and 11KDHT are potent agonists of the androgen receptor whereas 11OHT and 11OHDHT have milder potency. StAR=steroidogenic acute regulatory protein; HSD3B2=3β-hydroxysteroid dehydrogenase type II; CYP11A1, CYP17A1, CYP11B1=cytochrome P450 enzymes
Hyperinsulinism
Insulin resistance, and the consequent hyperinsulinism, have an important role in driving androgen synthesis in many endocrine tissues. Insulin acts as a co-gonadotrophin in the ovaries,36 impairs progesterone mediated inhibition of the gonadotrophin releasing hormone pulse generator,50 and facilitates synthesis of androgens in the adrenal glands by increasing adrenocorticotropic hormone stimulated steroidogenesis.51 AKR1C3 expression and activity in adipocytes is increased by insulin, contributing to increased synthesis of androgens in adipocytes in polycystic ovary syndrome.52 Insulin also inhibits sex hormone binding globulin, facilitating hyperandrogenism by increasing the percentage of free biologically active androgens.53 Excess production of androgens then stimulates hyperinsulinism, leading to a vicious cycle between androgen and insulin excess.7 54 Several studies have also implicated hyperandrogenism in the accumulation of abdominal and visceral adipose tissue in polycystic ovary syndrome55 56; this hyperandrogenism further drives insulin resistance and consequent production of androgens (figure 1).
In common with hyperandrogenism, insulin resistance is not a universal feature of polycystic ovary syndrome, although a systematic review of hyperinsulinaemic-euglycaemic clamp studies of 1224 women with polycystic ovary syndrome and 741 controls showed that insulin sensitivity was lower in women with polycystic ovary syndrome than in controls (mean effect size −27%, 99% confidence interval −21 to −33).57 Studies exploring steroid metabolomics in patients with polycystic ovary syndrome might give more information. One such cross sectional study (n=488) combining machine learning with mass spectrometry multisteroid profiling has identified three distinct groups of patients based on the predominant source of androgens.58 These subgroups have distinct steroid metabolomes and risk of metabolic complications: a gonadal derived classical androgen excess group, an adrenal derived androgen excess group (comprising 11-oxygenated androgens), and a group with comparably mild androgen excess.58 The adrenal derived androgen group had the highest rates of hirsutism, insulin resistance, and type 2 diabetes. These insights challenge our understanding of polycystic ovary syndrome as one entity and might prompt a reconsideration of the classification of the disease based on the metabolomic signature.
Changes in adipocyte structure and function
Changes in white adipose tissue morphology and function is seen in women with polycystic ovary syndrome, including enlarged adipocytes, reduced lipoprotein lipase activity,59 and increased secretion of proinflammatory cytokines.60 The function of brown adipose tissue might also be disrupted because women with polycystic ovary syndrome showed reduced postprandial thermogenesis compared with controls matched for body mass index.61 This defect could be driven by androgen excess, because prenatally androgenised sheep have reduced postprandial thermogenesis in adulthood,62 accompanied by reduced adipose expression of thermogenic uncoupling proteins and sympathetic activity. Adolescent prenatally androgenised sheep also showed reduced hepatic expression and circulating levels of fibroblast growth factor 21,63 a hormone that regulates adipocyte function, insulin sensitivity, and energy balance. Targeting expression of fibroblast growth factor 21 during an appropriate period in development might be a therapeutic option.
Gut microbiota and bile acid metabolism
Recent studies have implicated changes in the gut microbiome in the pathogenesis of polycystic ovary syndrome. Women with polycystic ovary syndrome have higher intestinal levels of Bacteroides vulgatus and lower levels of glycodeoxycholic acid and tauroursodeoxycholic acid.64 Oral gavage of wild-type mice with faecal microbiota from individuals with polycystic ovary syndrome or pure B vulgatus caused insulin resistance, changes in bile acid metabolism, reduced secretion of interleukin 22, and disrupted oestrous cycle and ovarian morphology.64 Administration of interleukin 22 or glycodeoxycholic acid to mice treated with B vulgatus improved insulin sensitivity, testosterone levels, and oestrous cycles. Hence modifying the gut microbiota or bile acid metabolism, increasing levels of interleukin 22, or a combination of these actions, might be therapeutically valuable in polycystic ovary syndrome.64
Insights from genome-wide association studies
Genome-wide association studies have identified numerous susceptibility loci for polycystic ovary syndrome, including 11 in Han Chinese populations,65 66 eight in European populations,67 68 and eight in a Korean population.69 Robust candidate susceptibility loci are near genes belonging to metabolic (insulin receptor (INSR), insulin gene-variable number of tandem repeats (INS-VNTR), and DENN domain containing protein 1A (DENND1A))70 and neuroendocrine (follicle stimulating hormone receptor, luteinising hormone receptor, and thyroid adenoma associated (THADA)) pathways.70 Meta-analyses of genome-wide association studies have shown that the genetic architecture of polycystic ovary syndrome is consistent across different diagnostic criteria and ethnic groups.71 72 These observations indicate a shared ancestry for polycystic ovary syndrome and reinforce the importance of neuroendocrine and metabolic pathways in the pathogenesis of the disease.
Developmental programming
Genetic loci identified by genome-wide association studies currently account for only 10% of the known heritability (about 70%) of polycystic ovary syndrome,73 74 suggesting other influences on the pathogenesis of the disease. Emerging evidence indicates that polycystic ovary syndrome might have its origins in utero, and thus could be subject to developmental programming and epigenetic modifications. Prenatal exposure to androgens in several preclinical models caused a permanent polycystic ovary syndrome-like phenotype postnatally.75–77 A programming effect might also persist transgenerationally, because pregnant mice treated with dihydrotestosterone produced female offspring with polycystic ovary syndrome-like phenotypes from the first to the third generations of offspring.78 Cautious interpretation is needed, however, because these models might not accurately reflect the human phenotype. Anti-müllerian hormone might also be involved in in utero programming: levels of anti-müllerian hormone increased significantly in pregnant women with polycystic ovary syndrome (P<0.001), and use of this hormone caused gonadotrophin releasing hormone neuronal hyperactivity and androgen excess in pregnant mice.79 Epigenetic mechanisms might also be involved in mediating susceptibility to polycystic ovary syndrome, with differential methylation patterns and microRNA expression detected in adipose tissue and ovarian tissue of patients with polycystic ovary syndrome compared with controls.80
Health risks
Polycystic ovary syndrome is well established as a reproductive disorder associated with hyperandrogenism, and is the leading cause of oligomenorrhoea and amenorrhoea.81 Patients with polycystic ovary syndrome are at increased risk of mental health disorders,82 83 endometrial cancer,84 and ovarian hyperstimulation syndrome after induction of ovulation.85 Consistent with our understanding of the pathogenesis, however, polycystic ovary syndrome is also recognised as a metabolic disorder, with long term health risks, including hypertension, type 2 diabetes, dyslipidaemia, insulin resistance, and obesity.1 These health risks could be associated with an increased risk of cardiovascular events86 and several adverse pregnancy outcomes.87 Although the reproductive aspects might diminish with age, metabolic features typically persist or can worsen.88
Therapeutic goals
Difficulty in losing weight, irregular menses, infertility, and excessive hair growth were the most important health problems reported by patients with polycystic ovary syndrome in an international survey.2 These problems should therefore represent the main targets for therapeutic intervention, although priority setting partnerships are still needed to help focus research priorities. Existing drug treatments have not been licensed specifically for polycystic ovary syndrome and are used off-label to target symptoms. Also, previous studies have not emphasised health related quality of life measures when evaluating response to treatment. An ideal treatment for polycystic ovary syndrome should look at the health risks, reduce key processes in the pathogenesis of the disease, and be responsive to the symptom profile and needs of the individual. Where relevant, treatments should reduce clinical and biochemical hyperandrogenism, restore ovulatory cycles and fertility, normalise the length of the menstrual cycle, improve insulin sensitivity, reduce weight and cardiometabolic risk, and improve condition specific quality of life.
Existing treatments
Non-pharmacological interventions
International guidelines highlight the importance of modifications to lifestyle in the management of the disease.3 Changes in lifestyle can improve fasting insulin levels and anthropometric outcomes, although benefits on hyperandrogenism are modest89 and adherence is often difficult to sustain in clinical practice. Data on reproductive benefits are limited,90 although a recent small randomised controlled trial of 68 women with polycystic ovary syndrome showed that a behavioural modification programme improved menstrual regularity compared with a minimal intervention group.91 Laser treatment might have a role in the treatment of facial hirsutism, although further trials are needed to confirm the benefits on quality of life and cost effectiveness.3
Contraceptive pill
In women not attempting to conceive, combined contraceptive pills are first line treatments for menstrual irregularity and hyperandrogenism.3 The oestrogen component increases sex hormone binding globulin, thus reducing free testosterone and improving hyperandrogenism. Because this stimulatory effect on hepatic production of proteins also causes hypercoagulability, ethinyloestradiol based contraceptive pills containing the lowest effective dose of oestrogen (eg, 20-30 μg of ethinyloestradiol) are recommended.3 Combined contraceptive pills containing newer, more physiological, oestrogenic compounds have recently been developed, and might have a lower risk of venous thromboembolism than ethinyloestradiol.92 The progestogen component reduces ovarian androgen production by inhibiting secretion of luteinising hormone and protects the endometrium from hyperplasia.93 Combined contraceptive pills containing androgenic progestogens, such as norethisterone, should be avoided because of the potential to aggravate hyperandrogenic symptoms. Furthermore, ethinyloestradiol based contraceptive pills containing cyproterone acetate, the most potent anti-androgenic progestogen, are not currently recommended as first line treatment because of the increased risk of venous thromboembolism.3 A recent systematic review of 19 randomised controlled trials, however, concluded that the ethinyloestradiol-cyproterone acetate combination improved serum testosterone (mean difference 0.38 nmol/L, 95% confidence interval 0.33 to 0.43) and hirsutism compared with conventional combined contraceptive pills.94 Thus combinations of cyproterone acetate and newer oestrogenic compounds might have the potential to improve hyperandrogenism in patients with polycystic ovary syndrome without the added risk of venous thromboembolism.
Anti-androgen agents
Currently available anti-androgen agents act by blocking androgen receptors (cyproterone acetate, spironolactone, and flutamide) or reducing production of androgens (finasteride and dutasteride). Guidance on specific preparations or doses in polycystic ovary syndrome is necessarily vague, because studies on these agents are few in number and small scale.3 Furthermore, although targeting excess production of androgens might be crucial to improved patient outcomes, the use of currently available anti-androgen drugs is limited by side effects. All anti-androgen drugs carry a risk of feminisation of a male fetus and therefore use must be restricted to patients with adequate contraception in place.3
Insulin sensitisers
Metformin modulates hepatic insulin sensitivity and glucose production by activating AMP activated protein kinase and AMP activated protein kinase independent pathways. More recently, metformin has also been shown to mediate its antiglycaemic effects by actions on the gastrointestinal tract and the gut microbiome.95 Metformin is used to manage weight and metabolic outcomes in adult women with polycystic ovary syndrome with a body mass index ≥25.3 Metformin might also improve ovulation and live birth rates but is less effective than clomifene citrate or letrozole.3 96 Nevertheless, because of its wide availability and low cost, metformin could still be valuable in improving reproductive outcomes in women with polycystic ovary syndrome, especially in healthcare economies where access to assisted reproduction is limited.
Thiazolidinediones improve insulin sensitivity by activating nuclear peroxisome proliferator activated receptor γ. A meta-analysis of eight randomised controled trials concluded that thiazolidinediones reduce insulin and fasting glucose levels in polycystic ovary syndrome, but do not seem to affect hirsutism scores or serum levels of androgens.97 Existing data on thiazolidinediones in polycystic ovary syndrome are limited. Thiazolidinediones are associated with intrauterine growth restriction in animal studies and weight gain in humans.98 Thiazolidinediones are thus not recommended for use in polycystic ovary syndrome outside of the licensed indication in type 2 diabetes. Preliminary studies suggest that the insulin sensitiser inositol might improve glycaemic control99 and new international guidelines recommend shared decision making on using inositol for its potential metabolic benefits in polycystic ovary syndrome. Specific doses, forms, or combinations of the substance, however, cannot be recommended because of a lack of high quality evidence.3
New therapeutic targets
Kisspeptin based treatment
Kisspeptin has a major role as a regulator of the hypothalamic-pituitary-gonadal axis, and therefore extensive efforts have been made in investigating the effects of kisspeptin based treatment in women with polycystic ovary syndrome and in other disorders of reproduction. KP54 and KP10 are the most studied native kisspeptins in humans and have been investigated for their potential role in optimising oocyte maturation in patients undergoing in vitro fertilisation.100 101 Although the two compounds bind to KISS1R with similar affinity, KP54 has a longer serum half-life than KP10 and a more profound effect on secretion of luteinising hormone.102 A bolus dose of KP54 induces oocyte maturation in patients with polycystic ovary syndrome without causing clinically significant ovarian hyperstimulation syndrome.100 101 Administration of a subcutaneous bolus injection of native kisspeptin is safe and well tolerated103 and also results in higher expression of gonadotrophin receptors (follicle stimulating hormone receptor and luteinising hormone receptor) and steroidogenic enzymes (including aromatase CYP19A1, steroidogenic acute regulatory protein, and 3β-hydroxysteroid dehydrogenase type II) in ovarian granulosa cells, potentially promoting an ovarian environment favouring progesterone synthesis and ovarian implantation.104
Use of KP54 as an ovulation induction agent, however, might be limited by tachyphylaxis.105 Because KP54 preferentially stimulates secretion of luteinising hormone over follicle stimulating hormone,106 concerns also exist that long term administration of kisspeptin might exacerbate pre-existing deficiency of follicle stimulating hormone in polycystic ovary syndrome.4 Nevertheless, KP54 effectively induced ovulation in neonatally androgenised rats but not in prenatal androgenisation or post-weaning androgenisation models.107 Simultaneous increases in luteinising hormone and follicle stimulating hormone were seen after KP54 use in the neonatal androgenisation model, suggesting that ovulation induced by kisspeptin is linked to its ability to stimulate increases in both luteinising hormone and follicle stimulating hormone.107 In a first-in-woman pilot study of 12 patients with polycystic ovary syndrome, twice daily use of KP54 over three weeks significantly increased levels of luteinising hormone (P=0.04) and oestradiol (P=0.03) but not follicle stimulating hormone or inhibin B.107 Two of the 12 women developed a dominant follicle with subsequent ovulation. Hence long term administration of KP54 might be suitable for follicular maturation in a subset of patients with polycystic ovary syndrome, but more studies are needed to identify the patient characteristics that predict response to treatment.
KISS1R agonists are currently in development with modifications that increase potency and are resistant to proteolytic degradation. KISS1R agonists might have a lower risk of tachyphylaxis because of their longer duration of action, allowing less frequent dosing. The KISS1R agonist, MVT-602, showed greater potency than KP54, increasing release of luteinising hormone in healthy women with a longer duration of gonadotrophin releasing hormone neuronal activation in vitro.108 When tested in patients with polycystic ovary syndrome, MVT-602 increased luteinising hormone with a similar amplitude but greater duration than KP54 in healthy women (area under the curve of luteinising hormone exposure 171.30 v 38.5 IU×h/L), similar to the natural mid-cycle surge in luteinising hormone.108 These findings warrant further investigation in polycystic ovary syndrome and in other female reproductive disorders.
Paradoxically, kisspeptin receptor antagonists have also been suggested as therapeutic agents in polycystic ovary syndrome based on their potential to normalise hypersecretion of luteinising hormone, restore folliculogenesis and ovulation, and improve ovarian hyperandrogenism.109 Existing KISS1R antagonists, such as P234 and P271, have inconsistent effects on kisspeptin induced stimulation of gonadotrophin releasing hormone-luteinising hormone across species.110 111 Compound 15 a is a small molecular KISS1R antagonist with antagonistic activity at the receptor and good permeability of the blood-brain barrier in rats.112 KISS1R antagonists have yet to be tested in humans, however, and concerns exist that these agents will overly suppress secretion of luteinising hormone and stop ovulation.4
Neurokinin 3 receptor antagonists
Inhibition of the neurokinin 3 receptor is believed to cause a tempered inhibition of gonadotrophin releasing hormone pulsatility without excessive reduction because of the presence of compensatory pathways.4 25 MLE4901 (also named AZD4901) had promising effects on levels of reproductive hormones in 65 women with polycystic ovary syndrome in a phase 2 randomised controlled trial.113 After seven days of treatment with MLE4901 80 mg/day, the area under the luteinising hormone curve was reduced by 52.0% (95% confidence interval 29.6% to 67.3%), total testosterone concentration was reduced by 28.7% (13.9% to 40.9%), and luteinising hormone pulses were reduced by 3.55 pulses/8 hours (2.0 to 5.1).113 MLE4901 was discontinued, however, because of increased levels of transaminases in some patients.114 115 Hepatotoxicity is believed to be specific to MLE4901 and has not been reported with other neurokinin 3 receptor antagonists.115
In a phase 2 randomised controlled trial in 64 women with polycystic ovary syndrome, treatment with the neurokinin 3 receptor antagonist, fezolinetant, for 12 weeks at 60 mg or 180 mg, reduced levels of testosterone by 17% (95% confidence interval −28.7% to −4.6%) and 33% (−45.91% to −20.4%), respectively, compared with 1% (−8.8% to 11.7%) with placebo.116 Levels of luteinising hormone but not follicle stimulating hormone were significantly reduced (P<0.001) in a dose dependent manner, reducing the ratio of luteinising hormone to follicle stimulating hormone.
Preclinical studies have also highlighted the potential metabolic benefits of neurokinin 3 receptor antagonists. In a dihydrotestosterone induced mouse model of polycystic ovary syndrome, treatment with neurokinin 3 receptor antagonists decreased body weight and adiposity.117 No changes in food intake or energy expenditure were seen, although an increased respiratory exchange ratio suggested that neurokinin 3 receptor antagonists cause a shift to a carbohydrate predominant utilisation of fuel.117 These promising observations suggest that neurokinin 3 receptor antagonists fulfil many of the properties of an ideal treatment for polycystic ovary syndrome, and further clinical trials are awaited with interest.
Dynorphin, γ-aminobutyric acid, and anti-müllerian hormone based treatment
When dynorphin binds to kappa opioid receptors, release of kisspeptin onto gonadotrophin releasing hormone neurons is inhibited, and therefore selective kappa receptor agonists with a central action might reduce gonadotrophin releasing hormone pulsatility.4 A new generation of peripherally selective kappa receptor agonists have been developed that might access brain regions, including the infundibular nucleus, by fenestrated capillaries in the median eminence.118 The kappa receptor agonist, difelikefalin, does not seem to cause the centrally mediated side effects of dysphoria and sedation of previous kappa receptor agonists, and has recently been approved in the US for the treatment of moderate-to-severe pruritus in adults undergoing haemodialysis.119 120 In a prenatally androgenised mouse model of polycystic ovary syndrome, difelikefalin reduced serum levels of luteinising hormone and testosterone, restored oestrous cyclicity and ovulation, and reduced overexpression of KISS1 mRNA in the hypothalamic preoptic area.121
Centrally acting GABAA antagonists might also benefit patients with polycystic ovary syndrome. Although weight gain could in part explain the increased incidence of polycystic ovary syndrome in women receiving sodium valproate, this drug also increases levels of GABAA in the central nervous system.122 In contrast, peripheral levels of GABA are reduced in patients with polycystic ovary syndrome,123 and enteral administration of GABAA reduced body mass index and levels of testosterone in a letrozole induced polycystic ovary syndrome model.124 Antagonism of the anti-müllerian hormone pathway might also be therapeutically useful; recent insights into the structural basis for binding of anti-müllerian hormone to anti-müllerian hormone receptor type 2 could facilitate the rational design of anti-müllerian hormone antagonists.125
Targeting key enzymes in steroidogenesis
AKR1C3 functions as the gatekeeper in classical and 11-oxygenated androgen synthesis by mediating enzymatic conversion of androstenedione to testosterone and 11-ketoandrostenedione to 11-ketotestosterone.6 Various AKR1C3 inhibitors have been developed, with mixed results for their antineoplastic effects and ability to inhibit prostaglandin F synthase activity in castration resistant prostate cancer, acute myeloid leukaemia, and oestrogen receptor positive breast cancers.126–128 Although steroidal based inhibitors of AKR1C3 are in development, the therapeutic potential in preclinical models of polycystic ovary syndrome has not been examined.129 Selective inhibition of 11β-HSD1 with BVT.2733 in a rodent model of polycystic ovary syndrome improved insulin resistance, reproductive hormone dysfunction, and polycystic ovarian morphology.37 These observations are encouraging but further preclinical work is needed before the potential therapeutic benefits of AKR1C3 and 11β-HSD1 inhibitors can be tested in patients.
Glucagon-like peptide 1 inhibitors
Glucagon-like peptide 1 (GLP-1) receptor agonists increase glucose dependent insulin secretion, suppress secretion of glucagon, and increase peripheral insulin sensitivity by weight loss (by stimulation of satiety) and suppression of inflammation in adipose tissue.130 Although these properties might be therapeutically attractive in patients with polycystic ovary syndrome, previous randomised controlled trials were largely small, single centre, and of limited duration.131 Nevertheless, in a network meta-analysis of 941 women with polycystic ovary syndrome and overweight or obesity, liraglutide was superior to metformin (mean difference −3.82, 95% confidence interval −4.44 to −3.20) and orlistat (−1.95, −3.74 to −0.16) in reducing body weight.132 Some studies showed that GLP-1 receptor agonists improved menstrual regularity or frequency, and that these improvements in menstrual frequency correlated with reduction in body weight.133 134 GLP-1 receptor agonists have also been shown to lower levels of androgens133 135 and improve markers of cardiovascular risk.136 137 A meta-analysis of eight randomised controlled trials concluded that GLP-1 agonists were more effective than metformin in improving homeostasis model assessment-insulin resistance (standard mean difference −0.40, 95% confidence interval −0.74 to −0.06), abdominal circumference (−0.45, −0.89 to −0.00), and body mass index (−1.02, −1.85 to −0.19), but not in improving menstrual frequency (0.15, –0.24 to 0.54) or serum levels of testosterone (0.64, –0.08 to 1.35).138 Newer longer acting GLP-1 analogues, such as semaglutide or dulaglutide,139 140 or dual GLP-1-glucose dependent insulinotropic polypeptide agonists, such as tirzepatide,141 could provide more therapeutic opportunities, with the potential benefits of greater effects on weight loss, longer duration of action, and improved adherence. Semaglutide, the only GLP-1 agonist currently available in an oral formulation, is being investigated in a clinical trial in adolescent girls with polycystic ovary syndrome and obesity (Treating PCOS With Semaglutide vs Active Lifestyle Intervention (TEAL), NCT03919929). More adequately powered trials with a focus on core outcomes of polycystic ovary syndrome142 are needed to establish whether these new drugs have a role in clinical management.
Sodium-glucose co-transporter inhibitors
Sodium-glucose co-transporter 2 inhibitors reduce reabsorption of glucose in the proximal convoluted tubules of the kidney, promoting excretion of urinary glucose, and also reduce weight and cardiovascular events in other populations.143 Current data in patients with polycystic ovary syndrome are limited to four small randomised controlled trials.144–148 Canagliflozin showed greater improvements in body mass index (P=0.006), basal metabolic rate (P=0.02), and fat mass (P=0.02) than metformin in women with polycystic ovary syndrome, but not in hormonal or metabolic parameters.144 In overweight and obese patients with polycystic ovary syndrome, combined canagliflozin-metformin treatment for three months produced greater reductions than metformin monotherapy in total testosterone (−0.33 v −0.18 ng/mL, P=0.02), area under the curve for glucose (−158.00 v 2.63 mmol/L×min, P=0.02), and the ratio of the area under the curve for insulin and glucose (−2.86 v 0.51, P=0.02),146 but no significant differences were found in menstrual frequency, body mass index, or homeostasis model assessment-insulin resistance between the treatment groups.146
Licogliflozin is a dual inhibitor of sodium-glucose co-transporter 1 (SGLT1) and 2 (SGLT2). Simultaneous SGLT1 and SGLT2 inhibition could provide more effective weight loss because SGLT1 inhibition alone stimulates intestinal secretion of GLP-1.131 In a phase 2 randomised controlled trial of 29 patients, licogliflozin reduced levels of androstenedione by 19%, dehydroepiandrosterone sulphate by 24%, and hyperinsulinaemia by 70% in women with polycystic ovary syndrome.148 The outcome of a recently completed randomised controlled trial of dapagliflozin on insulin resistance and serum levels of androgens in patients with polycystic ovary syndrome (Dapagliflozin Efficacy and Action in PCOS (DEAP), NCT04213677) is awaited with interest. Table 1 summarises the emerging treatments for polycystic ovary syndrome described in this review.
Emerging drug treatments for polycystic ovary syndrome
Guidelines
Guidelines on polycystic ovary syndrome vary in their methodological quality, approach to diagnosis, approach to screening for health risks, and recommendations for the use of drug treatments.149 The 2023 update to the international polycystic ovary syndrome guidelines, which uses consensus methodology and clear grading systems for clinical recommendations, has now been released.3 These evidence based guidelines were developed after consultation with international multidisciplinary and consumer bodies to support clinicians and patients in the diagnosis and management of polycystic ovary syndrome and reduce variation in care.
Conclusions
Polycystic ovary syndrome is a common reproductive and metabolic disorder resulting from polygenic and environmental influences. Key pathological changes include neuroendocrine dysregulation, excess production of androgens, insulin resistance, and changes in adipose tissue biology, with variation in dysfunction of these pathways contributing to differences in phenotypic expression and severity of the disease. Advances in genetic understanding, together with new techniques to assess the steroid metabolome, have identified new biological targets, challenged the perception of polycystic ovary syndrome as one entity, and could facilitate an individualised approach to long term cardiometabolic surveillance based on the metabolomic signature. These advances could, for the first time, enable the development of specific drug treatments for the disorder based on an improved understanding of the underlying pathophysiology. Well designed, multicentre, patient centred clinical trials of neurokinin receptor antagonists, kisspeptin based treatments, and repurposed antidiabetic drugs are now needed to investigate new therapeutic options for polycystic ovary syndrome.
Questions for future research
Should polycystic ovary syndrome be classified based on the steroid metabolomic signature, and specific treatments developed accordingly?
Does the steroid metabolome predict which patients are at increased risk of cardiometabolic disease?
Can reduction of 11-oxygenated androgens (eg, by inhibition of aldo-keto reductase type 1C3 (AKR1C3)) improve metabolic risk in patients with polycystic ovary syndrome?
Can later phase clinical trials of neurokinin 3 receptor antagonists show improvements in clinical hyperandrogenism and reproductive outcomes?
Women with PCOS are at more risk of getting type 2 diabetes if they are obese, have a family history of diabetes, don’t workout, are always stressed.
Polycystic ovary syndrome (PCOS) is a hormonal disorder that has now become common among women of reproductive age. The disorder leads to enlarged ovaries with small cysts on the outer edges. It has many symptoms, including facial hair, irregular periods, infertility among others. While most women suffering from PCOS are familiar with the common symptoms, many don’t know that PCOS makes them more vulnerable to type 2 diabetes.
As per the Center for Disease Control and Prevention (CDC), “Women with PCOS are often insulin resistant; their bodies can make insulinbut can’t use it effectively, increasing their risk fortype 2 diabetes.”
Another analysis unveiled as part of a study titled ‘Women’s Health Study’ by Harvard and Apple unveiled that women with PCOS are about four times more likely to have pre-diabetic conditions. The study asserts that they are also three times more likely to have type 2 diabetes.
The Indian Express recently quoted leading IVF expert and director of Zeeva Fertility – Dr Shweta Goswami saying, “PCOD and diabetes are interrelated because there is a hormonal imbalance happening in the body known as metabolic syndrome. PCOS disturbs women’s endocrine system”.
Who is at higher risk of PCOS and diabetes?
Women with PCOS are at more risk of getting type 2 diabetes if they are obese, have a family history of diabetes, don’t workout, are always stressed and are living an unhealthy lifestyle in general.
What are the precautionary measures that women with PCOS should take?
Women with PCOS should always keep a check on their weight. Weight management is extremely crucial to manage PCOS. They should also focus on stress management and inculcate the habit of exercising regularly. A good workout routine combined with healthy eating habits is the most effective way to deal with PCOS.
Women with polycystic ovary syndrome gained more weight annually than those without PCOS, and some lifestyle factors had a greater impact on weight gain with PCOS, according to study data.
“To our knowledge, this is the first time the contribution of extrinsic factors (including lifestyle and psychological factors and health care utilization) to weight gain has been examined in women with and without PCOS,” Lisa J. Moran, BSc (Hons), BND,PhD, APD, associate professor at the Monash Centre for Health Research and Implementation at Monash University School of Public Health in Melbourne, Australia, and colleagues wrote in a study published in Human Reproduction. “The prevalence of self-reported PCOS in this study was 8.7%, which is consistent with previous studies reporting 8.7% based on the National Institutes of Health diagnostic criteria. Using data from a large community-based longitudinal study, we found that women with PCOS had a 0.26 kg higher rate of annual weight gain and a 4.62 kg higher weight gain over 19 years than women without PCOS, even after adjusting for lifestyle factors.”
Women with PCOS have a higher annual weight gain than those without PCOS. Data were derived from Awoke MA, et al. Hum Reprod. 2021;doi:10.1093/humrep/deab239.
Researchers analyzed data from participants in the Australian Longitudinal Study on Women’s Health who were born from 1973 to 1978 and completed seven surveys from 1996 to 2015. Sociodemographic data, dietary intake, sitting time, physical activity, depression, anxiety and stress were self-reported. Participants reported whether they had a PCOS diagnosis in the last four surveys.
There were 7,180 women who completed all seven surveys, of which 8.7% reported having PCOS. Women with PCOS had a mean body weight in the first survey of 67.4 kg vs. 62.3 kg in those without PCOS. At 19 years, mean body weight increased to 82.9 kg for women with PCOS and 73.4 kg for those without PCOS.
In adjusted analysis, women with PCOS gained 4.6 kg more than those without PCOS at 19 years (P < .0001). The annual rate of weight increase was higher for women with PCOS vs. without PCOS (0.81 kg vs. 0.55 kg; P < .0001).
Each megajoule increase in energy intake (beta = 0.55; 95% CI, 0.41-0.68; P < .0001) and each hour increase of sitting time (beta = 0.24; 95% CI, 0.17-0.31; P < .0001) were associated with total weight gain for women with and without PCOS. Stress was the only psychological factor associated with weight change (beta = 0.97; 95% CI, 0.55-1.39; P < .0001). Weight gain was lower for each gram of fiber intake per day (beta = –0.08; 95% CI, –0.12 to –0.03; P = .001) and for women meeting physical activity guidelines compared with those not meeting guidelines (beta = –0.99; 95% CI, –1.33 to –0.65; P < .0001).
Three-way interaction testing between lifestyle and psychological factors, health care engagement and PCOS status and time was conducted to explore differences in weight-gain factors for women with PCOS and without PCOS. The rate of weight gain for women with PCOS was greatest for those with a higher energy intake (P = .006), greater consumption of foods with higher glycemic index (P = .025), sitting time of more than 10 hours per day (P = .041) and not meeting physical activity guidelines (P = .021).
“Our finding here of higher weight gain in women with PCOS and differentially greater impact of adverse lifestyle on weight gain in PCOS are important,” the researchers wrote. “These findings suggest that women with PCOS are biologically predisposed to weight gain overall, and that this is exacerbated disproportionately by adverse lifestyle factors. This aligns with patient experience from women with PCOS who reported perceived greater susceptibility for weight gain.”
The researchers said a greater focus on lifestyle interventions for preventing weight gain in women with PCOS is needed.
In a randomized, single-blind, 24-week study, participants assigned to dual therapy of 2 mg weekly of the GLP-1 receptor agonist exenatide (Bydureon, AstraZeneca) and 10 mg daily of the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) lost more weight than those taking either agent alone or those receiving dapagliflozin and metformin extended-release (Xigduo XL, AstraZeneca) or phentermine/topiramate extended-release (Qsymia, Vivus).
Dual therapy with exenatide and dapagliflozin was associated with greater weight loss in women with PCOS compared with dapagliflozin alone or dapagliflozin with metformin. Data were derived from Elkind-Hirsch KE, et al. J Clin Endocrinol Metab. 2021;doi:10.1210/clinem/dgab408.
“Greater improvements in participants with exenatide plus dapagliflozin may be explained in part by their different, and potentially complementary, mechanisms of action and confirm other studies showing that combining these two agents may exert stronger beneficial effects than each drug alone,” Karen Elkind-Hirsch, MSc, PhD, HCLD, scientific director of research at Woman’s Hospital Research Center in Baton Rouge, Louisiana, told Healio. “These findings, together with the convenience of once‐daily oral dosing and once‐weekly injection, support the use of these medications in this prediabetic population.”Karen Elkind-Hirsch
Elkind-Hirsch and colleagues recruited 119 premenopausal women aged 18 to 45 years with obesity and PCOS and without diabetes to participate in the study. Participants were randomly assigned to one of five therapies: exenatide alone, dapagliflozin alone, dual therapy of exenatide and dapagliflozin, combined dapagliflozin and metformin therapy, or the weight-loss medication phentermine/topiramate extended-release. Clinical, anthropometric and biochemical assessments were conducted at baseline, 12 weeks and 24 weeks.
The findings were published in TheJournal of Clinical Endocrinology & Metabolism.
Combination therapy produces greater weight loss
All treatment groups had improvements in fasting glucose, mean glucose, insulin sensitivity and insulin secretion at 24 weeks. Participants receiving combination exenatide and dapagliflozin had a greater reduction in mean blood glucose compared with the dapagliflozin, dapagliflozin and metformin, and phentermine/topiramate extended-release groups (P < .03). Those receiving exenatide or exenatide and dapagliflozin had larger increases in insulin secretion compared with the other three treatment groups (P < .04).
All five treatment groups had reductions in absolute body weight and BMI at 24 weeks, but the exenatide and dapagliflozin group had greater weight loss than those receiving only dapagliflozin or dapagliflozin and metformin (P = .005). Mean weight loss was 6.9% for those receiving exenatide and dapagliflozin therapy and 8% for those receiving phentermine/topiramate extended-release compared with 1.5% for participants receiving only dapagliflozin and 1.7% for those on dapagliflozin and metformin (P < .001).
“Modest weight loss is well known to reduce the risk of future diabetes in individuals with prediabetes,” Elkind-Hirsch said. “Therefore, it cannot be excluded that the modest reduction in body weight contributed in part to the improvement in insulin sensitivity in all groups. While phentermine/topiramate extended-release resulted in consistent significant changes in BMI and waist circumference, only exenatide and dapagliflozin and exenatide alone resulted in significant improvements in insulin secretion as well as mean blood glucose over an oral glucose tolerance test. This finding confirms the beneficial effect of GLP-1 agonists on beta-cell function in this obese prediabetic population.”
Long-term studies needed
Cholesterol, HDL cholesterol, LDL cholesterol and triglycerides-to-HDL ratio did not differ between the two groups. Triglycerides were lower at 24 weeks for the exenatide and dapagliflozin groups compared with phentermine/topiramate extended-release (P < .05). Both systolic and diastolic blood pressure decreased in all treatments at 24 weeks. There were no serious adverse events reported during the trial.
Elkind-Hirsch said the findings are encouraging, but more studies are needed to better establish long-term safety and efficacy of GLP-1 receptor agonists for women with PCOS.
“Future studies should include in their design consideration of the significant number of women with this disorder and the relatively young age of this population,” Elkind-Hirsch said.
As a medical student, one of the conditions that was hardest for me to get my head around was PCOS (polycystic ovarian syndrome). It took me several years of advanced training to understand the ins and outs of the syndrome.
PCOS is a complex hormonal condition that involves multiple organs systems. It’s is a clinical diagnosis, meaning that doctors diagnosis patients with PCOS based on symptoms – not on a specific lab test that is “positive of negative” for the condition. PCOS is diagnosed if a woman has two or more of the following symptoms:
Signs of too much male hormone (excess dark hair growth on chin, cystic acne or elevated testosterone on blood tests)
Menstrual cycles > 35 days apart
Enlarged ovaries on ultrasound
As hard as it was to grasp in med school, and as challenging as it is to explain it to my patients in a 10-minute office visit, it’s not surprising that there are a lot of misunderstandings about PCOS floating around.
Myth #1 “PCOS is caused by your ovaries”
PCOS is caused by a full body hormonal miscommunication – the actual polycystic ovaries are merely a symptom. There are many different metabolic issues going on that contribute to PCOS. The brain sends the ovary mixed signals causing it to secrete excess male hormones, which affects the delicate fluctuations of female hormone that trigger ovulation. At the same time, fat cells contribute to the problem by resisting insulin, triggering the body to make excess insulin when carbs are eaten. This insulin increase not only prompts the ovary to produce too much male hormone, but also causes weight gain. The ovaries can’t manage to ovulate because the hormones are all wrong.
Myth #2 “Women with PCOS are infertile”
Women with PCOS can have difficulty getting pregnant, but the infertility associated with PCOS is often easy to treat. Women who have PCOS and are overweight can often begin to ovulate regularly with very modest weight loss of even 10% of their body weight. Medication can also help; 50% of women with PCOS will conceive with clomiphene treatment (an inexpensive ovulation-inducing pill). Of women who conceive on clomiphene, the majority conceive within 4 months, so it should not be taken for an extended amount of time.
Myth #3″PCOS causes pain”
During a normal menstrual cycle, the chosen egg of the month begins to grow within a small follicle cyst on the ovary. When ovulation occurs, the egg escapes the cyst and makes a run for the fallopian tube, and its former cyst usually dissolves over time. In PCOS the ovaries are trying to ovulate but because of the body’s confused hormones, the ovulation cyst gets stuck and is unable to fully develop to the point it can spit out the egg, hence the ovary becomes swollen with underdeveloped cysts. These cysts cause the ovaries to become enlarged, but the cysts do not usually rupture or cause pain.
Myth #4 “Women with PCOS are overweight”
PCOS is often associated with obesity, but not always. At one time, PCOS was defined as having all three symptoms plus obesity, but we now recognize that there are different “types” of PCOS. You only need two of the three symptoms of PCOS to have the condition. The treatment of PCOS is based on the sub-type and your goal (for example, birth control pills do an excellent job of controlling the irregular cycles and treating the abnormal male hormone of PCOS, but would not be the best option for someone try to conceive). For overweight PCOS patients, a low carb diet with regular exercise is recommended. (My personal recommendation is the nutrition plan in The Obesity Code by Dr. Jason Fung)
Myth # 5 “PCOS patients have very high risk pregnancies”
I often have patients worry that since PCOS makes it challenging to get pregnant, it will also put them at super high risk during pregnancy. Once pregnant, PCOS patients are at an increased risk of gestational diabetes and high blood pressure, but most go on to have normal pregnancies. They do not have an increased risk of miscarriage as previously thought.
Around 10% of women meet the criteria for PCOS worldwide and our understanding of the condition and treatments has evolved over the last 20 years. If you have symptoms of PCOS, don’t get discouraged by the myths. Instead, talk to doctor about customized treatment of your condition.
Diagnosis of polycystic ovary syndrome (PCOS) is challenging, and there should be no rush to label an adolescent as having the condition before a thorough evaluation of symptoms, according to a leading endocrinologist who was speaking at the RCOG World Congress 2018 in Singapore.
“Common features of PCOS such as hirsutism, acne, and obesity are often present in otherwise ‘normal’ adolescents,” said Dr Veronique Celine Viardot-Foucault from the KK Women’s and Children’s Hospital, Singapore, adding that these features may not necessarily be indicative of PCOS.
Appropriate diagnosis of PCOS in adolescents should involve careful evaluation of symptoms such as menstrual irregularities, hyperandrogenism, and polycystic ovarian morphology, she said. Menstrual irregularities—including secondary amenorrhoea and oligomenorrhoea in girls beyond 2 years after menarche, or primary amenorrhoea in those who have completed puberty—may be indicative of androgen excess. [Horm Res Paediatr 2017;88:371-395]
As symptom such as acne is common in adolescence and usually transient, it may not be indicative of hyperandrogenism, said Viardot-Foucault. Also, isolated cases of acne and/or alopecia should not be considered as diagnostic criteria for PCOS in adolescence, but moderate or severe inflammatory acne that is unresponsive to topical therapy may require investigation of androgen excess. [Horm Res Paediatr 2017;88:371-395]
Another feature commonly seen with PCOS is hirsutism, which can be evaluated using the modified Ferriman–Gallwey (FG) scoring system. “However, the FG scoring system is not applicable to younger, perimenarchal patients [younger than 15 years old],” she advised, pointing out that biochemical evidence of hyperandrogenism is preferred in this group.
As there is no clear cut-off of testosterone levels for adolescents, biochemical hyperandrogenism should be defined based on the methodology used, informed Viardot-Foucault. “Ideally, to establish the existence of androgen excess, assaying for free testosterone levels is the gold standard as it is more sensitive than measuring the total testosterone levels,” she said. “But a downside of this is that it requires equilibrium dialysis techniques which are costly and not widely available.”
However, most commercial laboratories use direct analogue radio-immunoassay, which is notoriously inaccurate for measuring free testosterone, cautioned Viardot-Foucault. “If uncertain regarding the quality of the free testosterone assay, it is preferable to rely on calculated free testosterone, which has a good concordance and correlation with free testosterone levels measured by equilibrium dialysis methods,” she suggested. [J Clin Endocrinol Metab 1999;84:3666-3672]
Also, the value of measuring other androgens besides free testosterone in patients with PCOS is relatively low, although increased levels of dehydroepiandrosterone sulphate (DHEAS) have been observed in 30–35 percent of PCOS patients. [Ann N Y Acad Sci 2006;1092:130-137]
“Transabdominal pelvic ultrasound has a lower diagnostic accuracy,” said Viardot-Foucault. “The presence of polycystic ovarian morphology [on ultrasound] in an adolescent who does not have hyperandrogenism or oligo-anovulation does not indicate a diagnosis of PCOS.”
When menstrual irregularities are concerned, the first-line treatment should be cyclical progestogens when contraception is not required and there are no signs of hyperandrogenism, according to Viardot-Foucault. If there is clinical hyperandrogenism or a need for contraception in those sexually active, third-generation oral contraceptives such as ethinyl estradiol 30 µg can be considered.
“There is room for local treatment of hirsutism such as laser [hair removal, but only for patients beyond] 16 years old and [who are] at least 2 years post-menarche,” she said. “If there are metabolic complications, [patients should be referred] to the endocrinologist.”
There are some period problems that are unfortunately par for the course, like cramps, irritability, and bleeding more than you would like to be bleeding from your vagina.
But there are also some period problems that you should bring up to your doctor—just in case—because they’re a bit outside of what’s normally expected during menstruation. Here are some things to keep an eye out for.
1. You soak through a pad or tampon in an hour or less, your period lasts longer than seven days, or both.
The clinical term for an exceedingly heavy or long period is menorrhagia. These are basically horror movie-style periods, but some people don’t even realize this kind of bleeding is abnormal. “One of the biggest problems is someone being so used to heavy bleeding that she underplays the amount,” Lauren Streicher, M.D., an associate professor of clinical obstetrics and gynecology at Northwestern University Feinberg School of Medicine, tells SELF. “She’ll come in and say her periods aren’t too bad, then say she has to change her tampon every hour.” Passing clots larger than a quarter is also a sign your bleeding is too heavy, according to the Centers for Disease Control and Prevention (CDC).
WATCH THIS
Body Stories: Padma Lakshmi Tells the Story Behind Her Scar
It’s not just that bleeding way too much or for too long is messy and inconvenient. Losing more than the typical two to three tablespoons of blood during your period or bleeding for longer than seven days can lead to anemia, the CDC says. If you have anemia, you lack enough healthy red blood cells to get oxygen to all your tissues, so you may feel tired and weak, according to the Mayo Clinic.
Bleeding too much can also be a sign of various health issues, like uterine fibroids, which are benign growths in and on the uterus that can sometimes come along with problems like pelvic pain and frequent urination. Uterine polyps, which are growths on the inner lining of the uterus, can also cause heavy bleeding, as can cervical polyps, which are lumps that emerge from the cervix. Both types of polyps are typically non-cancerous but, in rare cases, may contain cancer cells.
The hormonal issue polycystic ovary syndrome (PCOS) can also cause heavy bleeding. Worse, this bleeding can strike after months of an MIA period. This gives your uterine lining a chance to build up over time, leading to an abnormally heavy period when it finally comes, Mary Jane Minkin, M.D., a clinical professor of obstetrics, gynecology, and reproductive sciences at Yale Medical School, tells SELF. PCOS can also cause symptoms like excess face and body hair or severe acne, thanks to high levels of male hormones.
Heavy menstrual bleeding could even be a sign of a disorder that causes you to lose too much blood, like idiopathic thrombocytopenic purpura (ITP). ITP usually comes along with other symptoms like easy and excessive bruising or a rash of reddish-purple dots on a person’s lower legs.
Clearly, figuring out what’s causing your heavy bleeding won’t be easy on your own, so you should see your doctor. They’ll typically ask about your other symptoms and perform exams to determine what exactly is going on, and treatment will depend on what you’re dealing with.
2. Your period brings days of pain that make it practically impossible to leave your bed.
Dr. Streicher’s rule is essentially that if you’re experiencing even an iota of period pain beyond what you’re fine with, it’s too much. The first step is typically to take nonsteroidal anti-inflammatory drugs, since they block hormone-like chemicals known as prostaglandins that cause uterine cramping. If that knocks out your cramps, you’re good to go. If you’re still curled up in the fetal position after a few hours, that’s a sign that you need evaluation, Dr. Streicher says. You’re dealing with dysmenorrhea (severe menstrual cramps), and doctors can help.
There are many different causes of overboard menstrual cramps. Fibroids are a common culprit. So is endometriosis, a condition many experts think happens when tissue lining the uterus travels outside of it and begins growing on other organs. (Other experts believe that tissue is actually different in that it can make its own estrogen, which can create painful inflammation in people with endometriosis.) In addition to causing extremely painful periods, endometriosis can lead to painful intercourse, occasional heavy periods, and infertility, according to the Mayo Clinic.
Adenomyosis, which happens when the endometrial tissue lining the uterus grows into the muscular walls of the organ, can also cause terrible menstrual pain, along with expelling big clots during your period and pain during intercourse.
3. You never know when your period is going to show up.
Pour one out for all the times you thought you’d have a period-free vacation, only for it to show up right as you hit the beach. Fun! Irregular periods could be due to a number of different things that are (at least somewhat) in your control, like stress and travel, Dr. Streicher says. But they can also happen because of various health conditions.
Take thyroid issues, for instance. Hypothyroidism, which is when your thyroid gland in your neck doesn’t produce enough hormones, can lead to an irregular period, according to the Mayo Clinic. It can also cause myriad other symptoms, like heavier than usual periods, fatigue, constipation, dry skin, weight gain, impaired memory, and more. Treatment typically involves taking medication that mimics the thyroid hormone.
On the flip side, hyperthyroidism, which is when your thyroid gland is overactive, can cause light or infrequent menstruation, along with issues like sudden weight loss, rapid heart rate, increased appetite, and more frequent bowel movements, according to the Mayo Clinic.
Irregular periods are also a sign of premature ovarian failure, which is when a person younger than 40 starts losing their normal ovarian function, according to the Mayo Clinic. It can also cause menopausal symptoms like hot flashes, night sweats, vaginal dryness, and difficulty conceiving. Doctors can offer estrogen therapy to relieve symptoms like hot flashes (typically in conjunction with progesterone to avoid the precancerous cells that may take hold if you take estrogen alone). They can also counsel you about the possibility of in vitro fertilization if you’d like to physically conceive and carry children in the future.
PCOS and uterine polyps be behind irregular bleeding, too.
4. Your period decides not to show up for a while.
While it’s true that you can sometimes randomly miss a period for reasons like stress, you shouldn’t just ignore a long-term missing period. Suddenly being period-free may feel blissful, but you’ll want to make sure there’s not a health issue going on, like PCOS, an eating disorder or excessive exercise affecting your menstruation…or, yes, pregnancy.
“If you’re menstruating normally then suddenly go months without a period, that’s not something to ignore,” Dr. Streicher says. If your period vanishes for three months or longer (this is known as amenorrhea), see your doctor for evaluation.
It’s worth noting that the use of some hormonal birth control methods—especially the hormonal IUD—can make your period basically disappear. Still, check with your doctor, just in case, when this happens.
5. You’re dealing with a lot of unexpected spotting between periods.
It could be something that’s ultimately pretty harmless, like a benign uterine or cervical polyp that’s causing bleeding between periods. But spotting is also a hallmark of pelvic inflammatory disease (PID), which is the result of sexually transmitted bacteria from infections like chlamydia and gonorrhea spreading to reproductive organs like your uterus, fallopian tubes, and ovaries. In addition, pelvic inflammatory disease can cause issues like fever, strange vaginal discharge that smells bad, and burning when you pee.
If you have PID, your doctor will first address the STI in question with antibiotics, says the CDC, then treat your partner for an STI if necessary. Pelvic inflammatory disease is a leading cause of chronic pelvic pain and infertility in women, so if you suspect you have it, treatment is of the essence.
More rarely, spotting in between periods can be a sign of cervical cancer, according to the Mayo Clinic. Cervical cancer can come along with watery, bloody discharge that might have a bad odor and pelvic pain, including during intercourse. Even though this likely isn’t your issue, you’ll want to get checked out, just in case. Treatment for cervical cancer may involve a hysterectomy, radiation, or chemotherapy.
6. You experience debilitating mood issues before your period.
When your estrogen and progesterone drop before your period, you may experience the typical mood swings that mark premenstrual syndrome (PMS). (Bear in mind that this may not be as drastic if you’re on hormonal birth control, which stabilizes your hormones throughout your cycle.)
But if you deal with severe mood swings, irritability, anger, a lack of enjoyment in things you usually enjoy, and other symptoms that affect your life, you may have premenstrual dysphoric disorder (PMDD). PMDD happens when you experience these symptoms in the week before your period, then they start getting better in the first few days of bleeding, and disappear in the weeks after your period. It’s listed in the DSM-5, the most recent version of the Diagnostic and Statistical Manual of Mental Disorders, for good reason: This psychological issue can completely turn your life upside down.
“If you suspect you have PMDD, the one thing I would encourage is keeping a daily record of the severity of your symptoms,” Dr. Minkin says. If these symptoms only rear their head the week before your period, PMDD might be your issue. If you realize you’re constantly dealing with them and your period just makes them worse, it might be premenstrual exacerbation, which is another way of saying you have a mental illness like depression that gets worse during your period.
Either way, a doctor can help. If you have PMDD, your doctor may have you take antidepressants in the timeframe when you usually experience symptoms, then stop once your period starts, Dr. Minkin says. (If you have premenstrual exacerbation, they may recommend staying on the antidepressants through the month and potentially upping your dosage in the week before your period.)
Or your doctor may suggest you go on birth control using a synthetic version of progesterone called drospirenone, Dr. Minin says, like Yaz and Beyaz. These are FDA-approved to treat PMDD. Though experts aren’t sure why they can be so successful in this arena, it may be because drospirenone reduces a person’s response to hormonal fluctuations. It’s also a diuretic, meaning it can flush out liquids that could otherwise cause fluid retention and contribute to annoying issues like bloating.
7. You have excruciating migraines before or during your period.
If migraines had any home training, they’d at least leave you alone when you’re about to get your period. Unfortunately, period migraines are indeed a thing.
It’s not that menstruation will just randomly cause migraines in unsuspecting people who have never had one, but women with a history of migraines may experience them before or during their periods, according to the Mayo Clinic, which adds that this may be due to estrogen fluctuations. “They tend to get the headache right as they go into their periods, and it seems to get better after they have had their menses for a day or two,” Dr. Minkin says.
If you’re dealing with this, your typical migraine medication may work for you. As you probably know if you’ve grappled with migraines, the treatment options are legion. They include pain-relieving medications to relieve symptoms ASAP and preventive drugs to ward off migraines altogether, according to the Mayo Clinic. In the former camp, you have choices like anti-nausea meds and triptans, which constrict swollen blood vessels and block pain pathways in the brain. In the latter, you’ve got meds like tricylic antidepressants, which affect brain chemicals like serotonin that may be implicated in migraines.
No matter what your period problem may be, you don’t have to suffer in silence.
You have no reason to feel embarrassed about your period—or the myriad problems that can come with it. After all, celebrities are out here talking about menstruation! Some pad commercials even—gasp—use red “blood,” these days! What a time to be alive.
If you’re having period problems, see your doctor for help. If they aren’t committed to relieving your symptoms, that’s a sign you should try to find a more sympathetic medical professional who can help you find the best treatment.
Read this before feeling weird about your nipples.
If you’ve ever noticed a rogue nipple hair, it probably prompted an array of emotions including confusion (um, hi, what are you doing here?) and annoyance (what does one even do about unwanted nipple hair?). But, in most cases, having hair around your nipples is actually perfectly ordinary. Think of it this way: You have hair all over you body, so your breasts shouldn’t be any exception.
Pretty much everyone has some level of hair on their breasts.
What people typically call “nipple hair” usually isn’t on the actual nipple at all. Instead, this hair often pops up on the areolae, aka the pigmented circles surrounding your nipples, and other non-nipple breast skin. “It is extremely common for women to have hair around the nipples,” Joshua Zeichner, M.D., a New York City-based board-certified dermatologist and director of cosmetic and clinical research in dermatology at Mount Sinai Medical Center, tells SELF.
The exact percentage of how many women have breast hair isn’t known, since this isn’t something that has been studied at large or that women usually report to their doctors. Still, women’s health expert Jennifer Wider, M.D., agrees, telling SELF that breast hair is “very common.”
But…why does it exist? Biologically speaking, humans likely developed body hair for many reasons, some of which scientists haven’t yet fully pinpointed. Hair around your nipples may be a holdover from when body hair was an important part of regulating your temperature, Dr. Zeichner says. Since things like air conditioning, heaters, and fuzzy sweaters can do that now, the hair around your nipples doesn’t seem to serve any present-day purpose. Consider it boob decoration.
There are a few factors that can determine how much (or how little) hair you have on your boobs.
Like any other kind of body hair, breast hair can vary in amount, thickness, and color from person to person. Similarly to your pubic hair, it can also look different from the hair on the rest of your body, Dr. Zeichner says.
You may notice more hair growing around your nipples if your hormones are fluctuating more than usual, like during pregnancy, Sherry A. Ross, M.D., a women’s health expert and author of She-ology: The Definitive Guide to Women’s Intimate Health. Period., tells SELF. The pregnancy-induced surge of estrogen can prolong your hair’s growth phase, so just like the hair on your head can seem especially long and lush when you’re expecting, so can the hair on your breasts, Dr. Wider explains. It’s all normal.
If you notice that you’re producing a lot more hair here than you used to, it could be a sign of a condition like polycystic ovary syndrome (PCOS), which can cause excessive hair growth on your face and body. This type of hair growth is known as hirsutism and can happen because of elevated male hormones, like testosterone, which are a common characteristic of PCOS, Dr. Ross says.
Keep in mind that having hair around your nipples without any other symptoms isn’t a sign of PCOS, Dr. Wider says. But if you’re noticing a lot more than usual and you’re also getting hair on your face, coupled with symptoms like bad acneand irregular periods, it’s worth flagging for your doctor. They can evaluate you and, if necessary, recommend treatment like birth control or other medications to prevent excessive hair growth.
Bottom line: Hair surrounding your nipples is usually just a part of having breasts.
There’s no reason to feel weird about it, or like your breasts need to be as smooth and hairless as a baby dolphin. But if you really can’t stand having breast hair, you can pluck it just like you would pluck your eyebrows (and it might hurt, just like it can with your eyebrows). The skin around your nipples is delicate and can be easily irritated, Dr. Zeichner says, so razors and wax are dicier options than simply tweezing.
If you have more hair around your nipples than you care to pluck, a dermatologist can talk to you about electrolysis (a procedure that involves inserting a tiny needle into the hair follicle and sending in an electric current to destroy the root) or laser hair removal, Dr. Zeichner says. (Just keep in mind that laser hair removal runs the risk of creating skin discoloration or other side effects, so you want to make sure you see someone who knows what they’re doing.)
Again, having hair around your nipples is super normal and not something you need to stress about or consider removing if it’s not bothering you. But, if it does bother you or it seems like a sign something’s up with your health, talk to your doctor to discuss ways you can nip any bothersome breast hair in the bud.
Karen Elkind-Hirsch
As a medical student, one of the conditions that was hardest for me to get my head around was PCOS (
ARYAN'S BLOG 
