Vitamin D and Ovulatory Dysfunction

Budi Wiweko
budi.wiweko01@ui.ac.id
budi.wiweko@gmail.com

Academic Health System Universitas Indonesia - Indonesian Medical Education and Research Institute (IMERI)
Faculty of Medicine Universitas Indonesia - Dr. Cipto Mangunkusumo General Hospital

Jakarta

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Vitamin D (VD) is a steroid hormone with a well-established role in calcium metabolism, bone modelling and remodelling
metabolic disorders, autoimmune conditions and reproductive system diseases. It is essential for maintaining mineral and
skeletal internal milieu. VD is hormonally active in the form of, ‘1,25-dihydroxyvitamin D (1,25(OH)2D)’, and is responsible for its
physiological actions facilitated by the VD receptor (VDR).

The role of VD in processes leading to reproduction is further confirmed by distribution of VD receptors (VDR) in male and
female reproductive systems . Hypovitaminosis (less than 20ng / dL of VD) is considered a cause of insulin resistance (IR),
metabolic diseases, polycystic ovary syndrome, and impaired ovarian responsiveness to assisted reproductive procedures.

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How do the calciotropic hormones (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and intact
parathyroid hormone (iPTH)) vary across the menstrual cycle and do cyclic patterns of
reproductive hormones (estradiol, progesterone, LH, FSH) differ by vitamin D status ?

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The concentrations of 25(OH)D do not
vary across the menstrual cycle

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 Concentration of total estradiol
(upper panels) and progesterone
(lower panels) by category of 25-
hydroxyvitamin D (25(OH)D; panel A,
C) and intact parathyroid hormone
(iPTH, panel B, D) across an ovulatory
cycle

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Polycystic Ovarian Syndrome (PCOS) likely has long-term effects
It is a disorder that typically has its onset early in life.

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Median density of healthy and atretic pre antral follicles in cortical biopsies
suggesting an intrinsic ovarian abnormality

80 73
70
60
50
Normal
40
Ovulatory PCO
30 27.4
Anovulatory PCO
20
11.4
10
0
Total follicle
Webber et al. Formation and early development of follicles in the polycystic ovary.
Lancet 2003

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There may be a higher initial population of primordial follicles (red line) or a slower rate of loss
by atresia (blue line)

Durlinger 2002

Primordial Mitosis Follicle Atresia

germ cells germ cells formation

Webber et al. Formation and early development of follicles in the polycystic ovary
Lancet 2003

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Int. J. Mol. Sci. 2021
 IS AMH A REGULATOR OF FOLLICULAR ATRESIA ?

AMH inhibits granulosa

cells apoptosis

David B. Seifer & Zaher Merhi. J Assist Reprod Genet, 2014

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 The differences of basal hormone levels, age and BMI
between PCOS and non-PCOS patients

n = 142

There were statistically significant differences between the PCOS and the control group in
median/ mean AMH, LH, and FSH levels.

Wiweko et al. J Assist Reprod Genet, 2014

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 ODDS RATIO OF EACH VARIABLE

n = 142

Patients with higher AMH levels ( ≥ 4.45 ng / mL) have 9.35 times higher possibility to suffer
from PCOS compared to patients with low AMH.

Wiweko et al. J Assist Reprod Genet, 2014

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 DNA Sequence Variation of the AMH (Anti-Mullerian Hormone) Gene Promoter:
Analysis of serum AMH and number of antral follicles in PCOS patients

Objective
To detect AMH gene promoter sequence variants

Method
The sample size was 114 patients, 60 PCOS patients and 54 non-PCOS patients as control
subjects.

Result
There were 60 point mutations in the AMH gene promoter. The number of mutations in the
gene promoter was correlated with serum AMH level and the number of antral follicles in
the PCOS group.

Suryandari, Kurniati, Wiweko, et al. Submitted to Fertil Steril, 2015

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The 3 mutations with the highest percentages in the study population were -
245 C/T (88.2 %), -444 A/G (17.9 %), and -674 G/A (100%).

Figure: Mapping of point variants on the AMH gene promoter

Suryandari, Kurniati, Wiweko, et al. Submitted to Fertil Steril, 2015

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 ROTTERDAM CRITERIA
2 out of 3 items

ANOV HA
Anovulation Hyperandrogen PCOS phenotype
1.Anov + HA + PCO
2.Anov + HA
PCO 3.Anov + PCO
Polycystic 4.HA + PCO

Which one is the most severe type ?

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 AMH levels of the four groups based on PCOS-related phenotypes

Indonesian people tend to be less hyperandrogenic compared to Caucasians

• Ovulatory PCOS patients had lower AMH levels compared to anovulatory PCOS patients
• Increased androgen levels have also been related with the increased production of AMH

Wiweko et al. J Assist Reprod Genet, 2014

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 Int. J. Mol. Sci. 2021

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 Int. J. Mol. Sci. 2021

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 Implantation-site vessels with endovascular trophoblast differed significantly among PCOS
phenotypes.

The overall incidence of microscopic placental lesions was significantly higher in the full-blown
and non-PCO phenotypes.

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n = 125

Phenotype 1 shows significantly higher AMH levels

(Kruskal–Wallis, p < 0.05) than other phenotypes.

Wiweko et al. BMC Res Notes, 2018

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Int. J. Mol. Sci. 2021
Role of vitamin D in human luteinized granulosa cells. Vitamin D down-regulates FSH receptor (FSHR) and antimu!llerian
hormone (AMH) receptor II (AMHR-II) mRNA levels. It also decreases Smad 1 / 5 / 8 phosphorylation and nuclear
translocation. Additionally, vitamin D induces 3-beta-hydroxysteroid dehydrogenase (3b-HSD) mRNA expression and
increases progesterone production and release.

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Association of vitamin D deficiency with factors
related to ovulatory dysfunction in polycystic
ovary syndrome (PCOS).

(Irani. Vitamin D and ovarian physiology)

Fertil Steril 2014.

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Crosstalk between advanced glycation end products and vitamin D: A compelling paradigm
for the treatment of ovarian dysfunction in PCOS

Merhi. Moll Cell Endocrinol, 2018

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Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in reproductive-aged women. In
addition to the reproductive consequences, PCOS is also characterized by a metabolic disorder, which may play
a part in the aetiology of anovulation and has important implications for long-term health as well. Vitamin D
deficiency is prevalent in PCOS and there is a close relationship between metabolic dysfunction and vitamin D
status in women with PCOS. The purpose of this systematic analysis is to evaluate the effect of vitamin D
supplementation on serum lipid profiles in patients with PCOS.

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Based on studies on animal models, vitamin D plays an essential role in reproduction by controlling
Ca and Mg levels. Despite these findings, the effects of vitamin D deficiency and supplementation
on the outcome of assisted reproductive techniques (ART) remain controversial. Therefore, the
aim of the present study was to assess the relationship between serum and follicular fluid 25-OH
vitamin D levels on reproductive outcomes of infertile women.

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 International evidence-based guideline for the assessment and management of
polycystic ovary syndrome 2018

ASSESSMENT AND TREATMENT OF INFERTILITY

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 High AMH PCOS

CC resistant
Metabolic syndrome

Insulin sensitizing agents (ISA)

Laparoscopic ovarian drilling (LOD)

VITAMIN D
LEPTIN

Decreasing serum

Ovulation Decreasing risk of metabolic syndrome

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 Take Home Messages

1. Mutation in AMH gene promoter cause increasing of serum AMH in PCOS patients which reduce
sensitivity of follicles toward FSH.

2. Serum AMH can be used as a tool for diagnosis, grading the diseases and treatment monitoring of
PCOS patients.

3. Indirect relationship between serum AMH and insulin resistance in PCOS patients leading them to
suffer from high risk of metabolic syndrome.

4. The use of vitamin D and leptin will down regulate AMH II receptor in granulosa cells.

5. Vitamin D induces Akt phosphorylation and downregulated RAGE thus attenuating the effect of AGEs
and potentially reducing insulin resistance at the granulosa cell.

6. Supplementation of high dose vitamin D with insulin sensitizer will improve PCOS and metabolic
syndrome symptoms.

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 Acknowledgement
Julianto Witjaksono, Ali Baziad, Andon Hestiantoro, Muharam Natadisastra, Kanadi Sumapraja,
Gita Pratama, Herbert Situmorang Eliza Mansyur, Tita Yuningsih, Siti Mariam, Endang Kurdiningsih,
Kresna Mutia, Pritta Iffanolia, Deka

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