Evaluation of Vitamin D in Women With PCOS and Sexual Dysfunction

BACKGROUND:

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive age
women with a prevalence as high as 15% using Rotterdam diagnostic criteria.1 PCOS is a
heterogeneous clinical disorder characterized primarily by chronic anovulation and
hyperandrogenism.2 A number of other metabolic and health complications are associated with
PCOS including obesity, insulin resistance, dyslipidemia, type 2 diabetes, cardiovascular
disease, and endometrial cancer.3

The clinical symptoms of PCOS including menstrual dysfunction, infertility, hirsutism,
alopecia, acne, and the possible increased risk of diabetes and cardiovascular disease have
been reported to be significant contributors to psychological morbidity and impact
health-related quality of life (HRQoL)4,5 including depression and anxiety,6,7 suicide
attempts,8 body dissatisfaction,9 eating disorders,10 lower overall health-related quality of
life11 and diminished sexual satisfaction.12,13

For women with PCOS, the changes in physical appearance and the associated mood disorders
appear to be deleterious for sexual function.6 Previous research in this area is scant, and
what has been done reveals a large number of women with PCOS (60%) reporting sexual
dysfunction and that the domains of desire and arousal are most commonly affected (in 98% -
99% of cases). Using the Changes in Sexual Functioning Questionnaire (CSFQ), others have
reported that women with PCOS were similar to control women in the number of sexual thoughts
and fantasies and in the frequency of sexual intercourse, but differed significantly with
lower orgasm/completion scores than control women.13 The existing research is limited by the
study populations used, which have consisted of infertile women with PCOS who have a high
prevalence of sexual dysfunction that may be more related to infertility and not an
underlying sexual dysfunction, and by the possible impact of depression and psychotropic
medications on sexual dysfunction.

Vitamin D deficiency (<20 ng/ml serum concentration of 25[OH]D), which affects from 67% to
85% of women,4 is closely linked to symptoms of PCOS. Observational studies have shown that
lower 25[OH]D levels are associated with insulin resistance, ovulatory and menstrual
irregularities, lower pregnancy success, hirsutism, hyperandrogenism, obesity, and elevated
cardiovascular disease risk factors14 as well as decreased HRQoL and depression in select
populations.15 Nonetheless, there is limited research exploring the implications of vitamin D
status and replacement on HRQoL issues including SDy.

The main physiologic role of vitamin D is to regulate calcium and phosphorus homeostasis and
to promote bone health. However, accumulating evidence suggests that vitamin D deficiency may
also be an important factor for many other diseases. Several mechanisms of action have been
proposed to explain the association between vitamin D and depression.

The role of calcitriol or 1,25 dihydroxy cholecalciferol, the bioactive form of vitamin D, in
brain tissue has been confirmed by the presence of vitamin D receptors (VDRs) and
hydroxylases in various brain regions. One area where VDRs and hydroxylases have been found
in the amygdala, the center of the limbic system, where behavior and emotions are
regulated.16 In addition, Vitamin D is involved in numerous brain processes including
neuroimmunomodulation, regulation of neurotrophic factors, neuroprotection, neuroplasticity
and brain development,16 making it biologically plausible that vitamin D might be associated
with HRQoL and SDy.

Although there has been an increase in awareness of the importance of sexual dysfunction and
QoL in women with PCOS, few studies have evaluated the outcomes of treatment for PCOS upon
sexual and subjective health status of women. Therapy has been directed at treating the
physical symptoms produced by chronic anovulation, hyperandrogenism and metabolic
disturbances associated with insulin resistance of PCOS. Treatment for PCOS has included oral
hypoglycemic agents, laparoscopic wedge resection, and cosmetic procedures, such as laser
hair removal, but the mainstay remains combined hormonal contraception.

The specific contribution of estrogens and progestogens in oral contraceptives is not fully
understood, particularly the latter as it has variable potency and androgenicity. In general,
the most commonly used progestins are the 19-testosterone derivatives. Newer oral
contraceptives, such as drospirenone, norgestimate, and desogestrel, contain less androgenic
progestins. Drospirenone is a 17-alpha spironolactone derivative progestin with
antiandrogenic and antimineralocorticoid activity. Studies have shown various benefits of
combined hormonal contraceptives for PCOS patients who are not pursuing fertility, e.g.,
management of endocrine and metabolic profiles, androgen levels, and endometrial cancer.5

Vitamin D supplementation has also been reported to improve glucose metabolism and menstrual
frequency in PCOS women17 and since Vitamin D deficiency is closely linked to PCOS and
depression, its supplementation has been suggested to possibly play an important part in the
treatment of PCOS and HRQoL and perhaps SDy.18

As such, the goal of this study is to evaluate the prevalence of sexual dysfunction and
assess the impact of treatment using oral contraceptives with Vitamin D on SDy in absence of
depression. The investigators anticipate this may provide a new treatment strategy in SDy
issues for women with PCOS.

METHODS:

The study will enroll 60 women diagnosed with PCOS and reporting SDy at the Wright State
Physicians (WSP) OB-GYN Practice and the WSP Family Medicine Practice.

All participants will take vitamin D 600IU/day (as recommended by the National Institutes of
Health's Office of Dietary Supplements) and will choose between hormonal and non-hormonal
contraceptive methods (target of 30 participants in each group). Participants will complete
three study visits (Initial, Month 3, and Month 6). Vitamin D levels will be drawn at the
beginning of the study and again at 3 and 6 months after initiation of vitamin D therapy.
Each participant will be asked to complete the Female Sexual Function Index (FSFI) and the
Beck Depression Inventory (BDI) prior to initiation of treatment and again at 6 months.

HUMAN SUBJECTS PROTECTION:

The PI is responsible for protection of human subjects. This protocol will be reviewed by the
WSU Institutional Review Board. Only subjects who meet study eligibility criteria will be
enrolled. All eligible participants will have the study explained to them. The informed
consent process will be conducted appropriately and the informed consent will be obtained
prior to proceeding with any study procedures.

The primary physician or the Principal Investigator and research associates will be the
individuals obtaining informed consent from patients. They will be uniform in their
explanations of the nature of the study to all patients who fit the selection criteria. Those
patients interested in participating will be given time to read over the informed consent.
The patients will be asked either in the clinic to be involved in the study. After the
informed consent is reviewed by the patient any remaining questions will be answered.

Adverse events will be reviewed and evaluated by the PI throughout the study. In the event
that any additional diagnoses are obtained during this study, the primary physician for the
patient will be notified. It will be their responsibility to notify the patient of these
diagnoses and any changes to management that may result.

Subjects' confidentiality will be protected. Participants will be assigned a unique
identification (ID) number for the study that will be used on data collection forms rather
than subjects' names. Only the minimum data necessary to conduct the study and meet the
objectives will be collected. Data will be stored in a secure database (REDCap19) that uses a
unique username and password for each team member. Data will be de-identified prior to
analysis.

SIGNIFICANCE OF THE STUDY IN RELATION TO HUMAN HEALTH (BENEFITS):

PCOS is the most common reproductive endocrine disorder that has a number of health quality
of life issues. The benefit of this study will be to identify SDy which is often overlooked
and may potentially be helped with Vit D and/or birth control.

POTENTIAL HAZARDS (RISKS):

The study questionnaires may evoke stressful feelings taking a psychosocial questionnaire. In
addition, there are rare potential risks related to OCPs including deep venous thrombosis,
and stroke.

Serious side effects of vitamin D include allergic reactions, swelling of the face, throat,
and tongue, dizziness, irregular or racing heart beat, dry mouth, headache, vomiting,
weakness and lack of energy, and fatigue

The risks of taking blood include pain, a bruise at the point where the blood is taken,
redness and swelling of the vein and infection, and a rare risk of fainting.

Inclusion Criteria:

- 1. Reproductive age

- 2. Have diagnosis of polycystic ovary syndrome by Rotterdam criteria (at least 2 of 3
criteria):

- a. Oligomenorrhea (cycles lasting > 35 days) or amenorrhea (< 3 cycles in last 6
months)

- b. Clinical signs of hyperandrogenism or elevated total testosterone level

- c. Polycystic appearing ovaries

- 3. Report sexual dysfunction

- 4. Have no evidence of depression

Exclusion Criteria:

- 1. Has chronic medical illness such as diabetes mellitus, hypertension, and previous
venous embolism

- 2. Taking any prescription medications for at least 3 months prior to entry into the
study with the exception of allergy or occasional pain medications

- 3. Has other etiologies of anovulation and hyperandrogenism, e.g., Cushings disease,
thyroid dysfunction, elevated prolactin levels, sighs of congenital adrenal
hyperplasia

- 4. Has any contraindications to hormonal contraception