AACE CLINICAL CASE REPORTS Vol 4 No. 5 September/October 2018 e427
Copyright © 2018 AACE
A KETOGENIC DIET MAY RESTORE FERTILITY IN WOMEN
WITH POLYCYSTIC OVARY SYNDROME: A CASE SERIES
Ula Abed Alwahab, MD1; Kevin M. Pantalone, DO1; Bartolome Burguera, MD, PhD1,2
Submitted for publication January 15, 2018
Accepted for publication April 15, 2018
From the 1Endocrinology & Metabolism Institute, Cleveland Clinic,
Cleveland, Ohio, and 2National Diabetes and Obesity Research Institute,
Address correspondence to Dr. Ula Abed Alwahab, Endocrinology &
Metabolism Institute, Cleveland Clinic, 9500 Euclid Avenue, /F20|,
Cleveland, OH 44195.
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2018 AACE.
Objective: Polycystic ovary syndrome (PCOS) is the
most common cause of infertility in women. We report the
clinical course of 4 women with PCOS trying to conceive
while following a ketogenic diet and assess their fecundity
after a period of 6 months.
Methods: The patients were followed once monthly in
a shared medical appointment setting for total of 6 months.
During each visit, the patients were assessed for weight
loss progression, menstrual regularity, and ovulation.
Results: The patients’ ages ranged from 24 to 29 years
old, their body mass indexes from 30.75 to 42.46 kg/m2,
and their duration of infertility from 1 to 4.5 years. All
patients were interested in pregnancy. The diagnosis of
PCOS was conrmed by an endocrinology consultation,
and the patients initiated a protein-sparing modied fast
(PSMF) diet. The PSMF diet entails a maximum daily total
carbohydrate intake of 20 g, fat intake up to 50 g, and an
approximate protein intake of about 1.5 g for each 1 kg of
ideal body weight. Metformin was continued if they were
already taking it, otherwise it was initiated with the PSMF
diet and titrated up to 500 mg twice daily. All 4 patients
adhered to the PSMF diet and were able to lose weight
(ranging from 19 to 36 lbs). All 4 also had irregular periods
prior to the PSMF diet, and resumed regular menstruation
shortly after starting the PSMF diet (ranging from 4 to 8
weeks). Two women were able to conceive spontaneously
with no ovulation induction needed.
Conclusion: The PSMF diet may have a promising
benet for women with PCOS by inducing weight loss
and facilitating ovulation. (AACE Clinical Case Rep.
BMI = body mass index; HSG = hysterosalpingogram;
PCOS = polycystic ovary syndrome; PSMF = protein-
sparing modied fast; SMA = shared medical appoint-
Polycystic ovary syndrome (PCOS) is the most
common cause of infertility in women. The major-
ity of women with PCOS have obesity (about 80%) (1)
and insulin resistance. Insulin resistance is considered
the main disturbance in women with PCOS (2). In fact,
recent studies show that hyperinsulinemia is present in
85% of patients with PCOS, specically 95% of women
with obesity and 65% of women with normal weight (3).
Increased insulin levels in patients with PCOS may, along
with high levels of luteinizing hormone, trigger the arrest
of follicular growth which contributes to anovulation (4).
Increased insulin resistance causes hyperglycemia leading
to hyperinsulinemia and it amplies luteinizing hormone
action on theca cells and further increases androgen
Patients with insulin resistance are often resistant to
ovulation induction (5). The administration of antidiabetic
drugs that lower insulin levels or improve insulin sensitiv-
ity has been associated with decreases in circulating andro-
gen levels and increases in ovulation rates (6,7). Obese
e428 PCOS Case Series, AACE Clinical Case Rep. 2018;4(No. 5) Copyright © 2018 AACE
mice with selective knockout of the insulin receptor in the
pituitary have resolution of normal gonadotropin secretion
and improved fertility, implying a direct role for insulin
action in PCOS (8).
Adipokines such as leptin are also important in control-
ling ovulatory function. This is well illustrated in patients
with anorexia nervosa or hypothalamic amenorrhea, where
gonadotropin secretion is suppressed with a subsequent
loss of ovulatory function. The fact that leptin replacement
alone can result in resumption of gonadotropin secretion,
follicular development, and in some cases ovulation in
women with hypothalamic amenorrhea, supports a direct
role for markers of fat and energy metabolism on reproduc-
tive function (9).
When dietary carbohydrate intake is restricted to a
level at which fat synthesis is minimal (a threshold that
varies from person to person), signs and symptoms of
insulin resistance improve or often disappear completely
(10). Recent studies have shown that a low-carbohydrate,
ketogenic diet can lead to weight loss and improvement in
insulin resistance (11).
The objective of this report is to characterize the meta-
bolic and reproductive proles of 8 patients with a diag-
nosis of PCOS who initiated a very low carbohydrate or
ketogenic diet, furthermore referred to as a protein-sparing
modied fast (PSMF) diet, for 6 months at our institution.
Our PCOS patients were referred by their primary care
physicians to the endocrinology clinic for the treatment of
PCOS, obesity, and insulin resistance. The patients were
enrolled in a shared medical appointment (SMA) program
that consisted of monthly appointments for PSMF diet
instruction at our clinic. Attendees were all women with
obesity (body mass index (BMI) ≥30 kg/m2), of childbear-
ing age (18 to 50 years), who had been clinically diagnosed
with PCOS (irregular periods, signs of hyperandrogen-
ism) and had completed laboratory tests with or without
The rst meeting of the SMA program mainly focused
on the rationale and implementation of the dietary interven-
tion via use of a PSMF diet book and handouts containing
suggestions on choice of appropriate foods. The PSMF diet
entails a daily total carbohydrate intake of no more than 20
g, fat intake of 50 g minimum, and an approximate protein
intake of about 1.5 g for each 1 kg of ideal body weight.
Example PSMF diet meals could be a low-carbohydrate
protein shake or 2 eggs and 3 strips of bacon for breakfast,
salad with a protein (chicken or sh) for lunch, 4 to 6 oz
of meat with low-carbohydrate vegetables for dinner, and
celery sticks with peanut butter, one hand-full of almonds,
one medium egg, or turkey cheese rolls as snacks.
During each subsequent monthly visit, a brief review
of the diet composition was provided. Patients underwent
a medication reconciliation and were also assessed for
their adherence to the diet, blood pressure, weight, labs,
and their reproductive history (menstrual cycles, ovulation
check by urine strips, and potential pregnancy). Each SMA
lasted 90 min. Patients were also encouraged to increase
their level of physical activity such as by walking at least
half an hour 3 times per week. The patients were always
reminded to stop the PSMF diet as soon as possible if they
discovered they were pregnant. Information about healthy
nutrition during pregnancy was also provided during
We reviewed the clinical course of the patients who
joined the classes and had a history of PCOS-related infer-
tility (unable to conceive after 1 year of unprotected sexual
intercourse). We also addressed their reproductive param-
eters and fertility changes during the 6-month period in
which the patients followed the PSMF diet. Four women
were not able to comply with the diet due to food prefer-
ence and are not included in this case series. A retrospective
chart review was conducted on 4 patients who were able to
adhere to the PSMF program. Each patient’s clinical course
was summarized in detail, and categorical and continuous
variables were summarized using percentages, medians,
and ranges. No signicant side effects to the PMSF diet
were reported by the patients.
As a group the patients had a median age of 25 years,
ranging from 20 to 29 years, median BMI of 35.4 kg/m2
with a range of 30.8 to 42.5 kg/m2, and a median percent
body weight loss at 6 months of 9% with a range of 8 to
20% body weight loss. The patients’ characteristics can be
seen in Table 1. The clinical courses of these 4 patients are
This 26-year-old woman with a 4.5-year history of
infertility and a BMI of 42.5 kg/m2 reported absent periods
and had received no prior ovulation induction therapy. Her
hysterosalpingogram (HSG) was normal; semen analysis
for her partner was not performed. The patient was never
on metformin therapy prior to starting this program; she
was prescribed 500 mg of metformin twice daily at the
beginning of the program. Her menstrual periods became
regular after 1 month of the program after losing only 3
lbs (1% of her weight), and she became pregnant 2 months
after nishing the program (after losing 8% of her weight).
Her initial weight was 279 lbs; her weight after 6 months
was 256 lbs.
This 29-year-old woman with a 2.5-year history of
infertility and a BMI of 33.3 kg/m2 had absent periods. She
reported having tried clomiphene citrate for 3 cycles with-
in the past year without successful conception. HSG and
semen analysis were completed and were both normal. The
patient was already taking metformin (500 mg twice daily)
PCOS Case Series, AACE Clinical Case Rep. 2018;4(No. 5) e429 Copyright © 2018 AACE
for the past 3 years before starting the PSMF diet program
with no improvement in her periods or anovulation. The
patient was asked to continue the metformin therapy. Her
menstrual periods became regular after 1 month (we do not
have a weight measurement at 1 month). She became preg-
nant 7 months after nishing the program and lost a total
of 36 lbs, or 20% of her total body weight, and she kept the
weight off prior to her pregnancy. Her initial weight was
176 lbs; her weight after 6 months was 140 lbs.
This 24-year-old woman had a 4.5-year history of infer-
tility. Her presenting BMI was 37.5 kg/m2. The patient’s
periods were absent. She had been taking metformin XR
at 500 mg twice daily for 3 years prior to enrolling in the
PSMF diet program with no improvement in her periods or
anovulation. She was asked to continue the metformin. The
patient never tried any ovulation induction therapy prior to
the program. Her menstrual periods became regular within
the rst month of the program during which she lost 10 lbs,
5% of her total body weight. The HSG noted a unilateral
fallopian tube blockage for which she was referred to the
gynecology department. No semen analysis of her partner
was performed. Her initial weight was 218 lbs; weight after
6 months was 197 lbs.
This was a 27-year-old woman with a 1-year history of
infertility. Her presenting BMI was 30.8 kg/m2. The patient
had irregular menstrual periods. The patient could not
tolerate metformin due to severe diarrhea prior to the start
of the program so metformin was not restarted in her case.
The patient had never tried any ovulation induction therapy
prior to the program. Her periods became regular 2 months
after starting the PSMF diet program at which point she
had lost 9 lbs, 5% of her total body weight. Her HSG was
normal as well as the semen analysis of her partner. The
patient was lost to follow up after the program. Her initial
weight was 190 lbs; weight after 6 months was 171 lbs. A
comparison of key results for the patients is presented in
This small case series demonstrates that a very-
low carbohydrate diet may be helpful in reversing insu-
lin resistance and the subsequent aberrant ovulatory
cycles observed in women with obesity and PCOS. Our
series found similar results to a pilot study conducted by
Mavropolous et al (12) as well as a case series by Douglas
et al (13).
However, in our case review, we observed the resump-
tion of menstrual period regularity with minimal weight
loss within 1 month of starting the diet, suggesting that
the weight loss alone was not solely responsible for restor-
ing the ovulatory cycles. This observation may, in part, be
explained by a reduction in the levels of insulin, which has
been implicated to play a prominent role in the ovarian
pathophysiology observed in PCOS patients.
Patients following a limited-calorie diet tend to have
an increase in their ghrelin levels during the rst few weeks
of following the diet (14). Moreover, PCOS patients have
been shown to have a ghrelin regulation problem fasting,
postprandial, at baseline, and after signicant weight loss
compared to their non-PCOS peers when both undergo the
same weight-loss program (14). The increase in ghrelin
Patient Baseline Characteristics
Patient Age BMI
infertility Periods HSG
1 26 42.46 4.5 years absent normal not done
9.54 16.7 31 0.47
2 29 33.27 2.5 years irregular normal normal
13.25 22.0 101 2.20
3 24 37.45 4.5 years absent unilateral
block not done
not done 14.5 82 1.97
4 20 30.75 1 year irregular not done normal
8.75 17.9 68 1.24
Abbreviations: AMH: anti-müllerian hormone; BMI = body mass index; HSG = hysterosalpingogram; TSH = thyroid-stimulating
e430 PCOS Case Series, AACE Clinical Case Rep. 2018;4(No. 5) Copyright © 2018 AACE
levels that accompanies calorie restriction can impact the
observed compliance with any dietary program.
In light of these facts, assistance with appetite control
would seem to be a more ideal approach to help PCOS
patients who want to lose weight. However, as all of our
patients were interested in pregnancy, appetite suppres-
sants were not prescribed as none of these medications
have been proven to be safe during pregnancy. Therefore,
we propose the best solution for this population of patients
is a ketogenic diet. Elevated circulating free fatty acids
in ketosis may actually reduce food intake and glucose
production through actions on specic hypothalamic path-
ways. It has been suggested that this effect could be medi-
ated by increased cellular concentrations of long-chain
fatty acid-coenzyme A esters in the arcuate nucleus of the
hypothalamus by reducing the expression of neuropeptide
Y. Neuropeptide Y is an important orexigenic neuropep-
tide that is a downstream target of leptin and insulin in the
Moreover, ketosis has been reported to affect the
gastrointestinal regulation of satiety (17). In a series of
39 patients who followed a ketogenic diet for 8 weeks
followed by a 2-week refeeding phase, ghrelin was noted
to be suppressed during the ketogenic period. Glucose and
free fatty acids were higher, and amylin, leptin, and subjec-
tive ratings of appetite were reported to be lower during
We allowed patients to stay on the PSMF diet for a
6-month period or until they reached their weight loss
goal. After the 6-month period, we asked them to switch
to a modied PSMF diet program where a more liberal
amount of carbohydrate was allowed (90 g/day of carbohy-
drate) to maintain the weight loss (18). However, we also
educated the patients to stop the ketogenic diet in the event
they became pregnant and we provided a healthy dietary
program for them to follow during pregnancy to help avoid
regaining the extra weight.
There is very limited data regarding the safety of
ketosis during pregnancy. However, there is no reported
evidence that ketosis is harmful to the pregnant woman
or the fetus. In fact, urine ketone levels bear little rela-
tion to blood levels once acetoacetate values are as low
as 0.1 mmol/L, and therefore a positive urinary ketone
test result during pregnancy does not necessarily indicate
harmful blood ketone levels (19). Moreover, at least 13%
of the total cerebral oxygen consumption at 2 to 4 weeks of
neonatal life comes from ketones (20), and during the rst
few days of life, ketones account for 25% of their body’s
caloric needs (21).
While metformin may have played a role in restor-
ing normal ovulatory cycles and allowing for pregnancy, 2
patients in our series were already on metformin for years
with no ovulatory benet and were only able to resume
regular menstruation/ovulatory periods after initiating
the PSMF diet. Also, patient number 4 was never given
metformin with the diet as she had a history of gastric
intolerance to metformin. Moreover, metformin was able
to restore regular menses and ovulation in only 25 to 50%
of PCOS cases in the largest case series reported in the
literature (22,23). Mavropolous et al (12) also showed a
ketogenic diet had effects without using metformin, so we
conclude in our cases that the diet was more effective in
restoring regular periods than metformin. However, larger
studies are still needed to compare the effects of diet to
metformin and also to see if combining both treatments has
an additive benet.
PSMF or other ketogenic diet interventions may
also be reasonable treatment approaches for patients with
PCOS who are not seeking fertility. Oral birth control pills
that are usually used to regulate periods in PCOS patients
are not always a safe option. For example, one series of
9 women with PCOS and 10 age- and weight-matched
control women were studied before and during the third
month of therapy with a low-dose norethindrone-contain-
ing triphasic combination oral contraceptive pill (24).
Using the hyperglycemic clamp technique the researchers
found the short-term therapy with the pill (for 3 months)
resulted in a decline in the PCOS patients’ insulin sensi-
tivity index. Insulin resistance parameters have also been
shown to worsen with oral contraceptive pills even if the
patient was on metformin concomitantly (25).
In addition, oral contraceptives can increase the risk
of venous thromboembolism in obese patients. In the
Multiple Environmental and Genetic Assessment (MEGA)
study (26), 3,834 patients on oral contraceptives with a
rst venous thrombosis and 4,683 control subjects were
Weight loss in 6
months in lbs
(% of total)
Initial weight /
after 6 months
1 23 (8%) 279 / 256 regular no yes
2 36 (20%) 176 / 140 regular no yes
3 21 (9%) 218 / 197 regular no no
4 19 (10%) 190 / 171 regular no no
PCOS Case Series, AACE Clinical Case Rep. 2018;4(No. 5) e431 Copyright © 2018 AACE
included. All were non-pregnant and without active malig-
nancies. Relative to those with a normal BMI (<25 kg/m2),
overweight women (BMI from 25 to 29.9 kg/m2) had an
increased risk of venous thrombosis by 1.7 fold and obese
women (BMI ≥30 kg/m2) had increased risk of 2.4 fold.
Limitations to this study are the size of the popula-
tion and the lack of a comparison group of PCOS patients
treated conventionally rather than with the ketogenic diet.
An additional limitation is the lack of lab data (hormonal
and metabolic) pre- and post-treatment with the ketogenic
diet. This additional information would be very important
in order to identify the underlying mechanisms by which
our observations are occurring. This should be investigated
in a future prospective study.
This report highlights the ketogenic diet as a potential
treatment option in the PCOS patient population, which
may potentially assist with restoring normal menstrual
cycles, ovulation, and thus improving fertility. In some
instances, the ketogenic diet approach may even negate the
need for more expensive (and potentially more harmful)
forms of fertility treatments. Our ndings support the need
for a larger prospective study comparing a low-carbohy-
drate ketogenic diet to other diets used for PCOS, address-
ing whether the ketogenic diet would have a faster effect on
ovulation and fertility. Another idea would be to compare
PCOS patients treated with a ketogenic diet alone to those
treated with metformin, ovulation-inducing therapies, or
both and see if any modality is superior to the others in
restoring menses and ovulation and if combining different
modalities would have any additive benets.
The authors have no multiplicity of interest to disclose.
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