Infertility Treatment in India | Best Fertility Specialist

GREETINGS FROM

PONNI HOSPITAL

www.ponnitesttubebabycentre.com

Dr. YAZHINI SELVARAJ MD,DGO,

Diploma reproductive medicine (Germany)Rtd Asst. Professor .O&G Department

Government Rajaji Hospital and

Madurai Medical Collage - Madurai

Managing Director, Ponni Hospital Fertility's & Research Centre - Maduraiwww.ponnitesttubebabycentre.com

Historical PerspectiveOur ancestors spent a considerable amount of time in

the sunThey developed skin pigmentation appropriate for

the UV conditions in early fall: pale enough for vitamin D production, yet dark enough to reduce the risk of DNA damage and destruction of folate

Our relationship with the sun changed with increased urbanization and migration


Production of Vitamin D from Ultraviolet-B (UVB) Radiation

UVB radiation (290-315 nm) converts 7-dehydrocholesterol into pre-vitamin D

Previtamin D3 undergoes a thermal isomerization that results in the formation of vitamin D3 (25 hydroxyvitamin D (25(OH)D))

This is converted to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in the liver and kidney


Cholecalciferol – naturally occurring form

made in skin when exposed to sunlight (UVB rays 290 - 310 nm).

transported to liver, metabolized into calcidiol.

Calcidiol (25-OH-D) – Prehormone, storage form of vit

D Steroid-like properties Reliable indicator of vit D

adequacy Calcitriol (1,25-

dihydroxyvitamin D) – made from calcidiol in kidneys

and other tissues


Obese people are more likely to be vitamin D deficient and vitaminD deficiency seems to predispose people to obesity

People living at higher latitudes


Darker skin types• Melanin is an excellent

sunscreen

• On average, African Americans have levels of 25(OH)D that are 1/2 that of Caucasian Americans

Elderly people aged 62-80 synthesize 1/3rd Vit D as a person aged 22-30 after the same sun exposure


• Inflammatory bowel disease• Celiac disease• Cystic fibrosis• Pancreatic insufficiency

Complete clothing coverage Malabsorption

Who is at increased risk of Vit D deficiency?

Medications Anticonvulsants: Dilantin,

Phenobarbital Bile acid sequestrants:

Cholestyramine Cimetidine, Ranitidine Corticosteroids Antacids Calcium channel blockers Mineral oil, Orlistat

VDR polymorphisms ‘ff” genotype: Graves’ disease ↑

and Hashimoto’s thyroiditis ‘bb ’ genotype: colon & ↑

prostate cancer ‘SS’ genotype: RR of 3.2 for

breast cancer in Latina women


Vitamin D status in India

Vitamin D deficiency is epidemic in India despite plenty of sunshine.

Studies have documented low 25(OH)D level in the Indian population despite abundant sunshine.

Low dietary Vitamin D intake is also been documented.


How prevalent is Vit D deficiency in India ?

Prevalence varying from 50-100%INDIA

Latitude of 22° 00’N Longitude of 77° 00’W

Why does this happen?Changing lifestylesDress codeUrban- less sun exposureRural- less calcium intakeAvoiding the sunSunscreensDark skin


Why in India?

Two problems:Color of our skinUnfortified dairy products


Vitamin D & calcium metabolism


Vitamin D mediates its actions via binding to Vitamin D

receptors (VDRs)

VDRs:

found practically in every human tissue.

affect the function of up to 1000 different genes

controls protein synthesis and cell growth and

differentiation

Vitamin D Extra-Osseous Actions?

Journal of American College of Cardiology: 2008, 52, 1949-56www.ponnitesttubebabycentre.com

Endocrine, Paracrine & Intracrine Functions Of Vit D

Extra-renal 1,25(OH)2 D1 alpha-hydroxylase detected in: skin vascular smooth muscle monocytes/macrophages lymph nodes colon pancreas (islets) adrenal medulla brain placenta prostate cells breast cells

Local prodn of 1,25(OH)2D in breast, colon, prostate, and other tissues

regulates a variety of genes that control proliferation, including p21 and p27,

as well as genes that inhibit angiogenesis and induce differentiation and

apoptosis.

Vitamin-D Deficiency: Bone What are the problems in india

In adults: osteomalacia Mainly symptoms

In growing children: rickets Mainly signs


Vitamin D : SourceFood ug/serv

e (1ug=40 IU)

%AI (19-50y age)

Salmon 3.5 oz,

9.0 180

Tuna in oil, 3 oz

5.0 100

Milk skim 1 cup*

2.45 49

Cereal, ¾ cup*

1.0 20

Egg, 1 0.5 10

*Fortified; AI-Adequate Intake. [AI double for 51-70y]


Spectrum of Vit D status The term “vitamin D deficiency” =severe vit D deficient state

assoc with osteomalacia“Vitamin D insufficiency / inadequacy / hypovitaminosis D” =

mild & moderate deficiency 25(OH)D levels 20 - 30 ng/ml, assoc with Secondary hyperparathyroidism (SHPT) & negative skeletal consequences.

25(OH)D levels >30 ng/ml considered normal


For Caucasians10 to 30 minutes on the hands, arms, and face three times per week.

For Dark skinned peopleNeed 5–10 times longer sun exposure than whites depending on skin type

Vitamin D: Recommended Sunlight Exposure Time

21www.ponnitesttubebabycentre.com

Vitamin D & SunlightGeography, season, time, sky cover, and barriers between the

sun and skin are all reasons why people do not produce as much vitamin D3 as they need.

The sun’s rays must be at a precise angle for UVB radiation to reach the surface of the planet.

Adequate amounts of UVB light can only be absorbed between 10:00 a.m. and 2:00 p.m.

Clouds reduce penetration by 50%.

UVB light does not go through glass.

22www.ponnitesttubebabycentre.com

Vitamin D status in middle age group (20 - 45 years)

Important to assess Vit D status in this group – as peak bone mass is achieved at around 30 years age).

Rural population have better Vit D status compared to urban population. Most of rural workers were agriculture laborers.

Soldiers and subjects of Indian Para military forces who undergo rigorous outdoor exercise in sunlight with high dietary Ca intake had higher Vit D status.

Vitamin D status in post menopausal women

There are two studies to show the low Vitamin D status.

It has important implications in interpretations of bone mineral density and therapy of post menopausal osteoporosis.

Paul TV, et al. Endocr Pract 2008;14:665-71.

Arya V, et al. Osteoporos Int 2004;15:56-61.

Panwar B, Punia D. Nutr Health 2000;14:217–23.


Vitamin D status in higher altitude and latitudeClouds retain 10% of rays, snow absorbs 20% and

reflects rest

UV-B rays ses by 10% per kilometer above sea level, ↑but the solar zenith angle is obtuse.

The studies from Kashmir valley have shown lower vitamin D status.

. Zargar AH, et al.Vitamin D status in apparently healthy adults in Kashmir Valley of Indian subcontinent. Postgrad Med J 2007;83:713-6


Rickets

Osteomalacia

Osteoporosis

Chronic kidney disease

Hepatic failure

Bariatric surgery

Antiseizure medications

Antifungals, e.g. ketoconazole

Pregnant and lactating women

Older adults with history of falls or nontraumatic fractures

Obese children and adults (BMI 30 kg/m2)

Hyperparathyroidism

Glucocorticoids

Tuberculosis

Crohn’s disease


Age (Year)

IOM(Institute of Medicine)2010 guideline

Endocrine Society2011 guideline

IU/ Day RDAng/ml

IU/ Day RDAng/ml

1-18 600 20 1000 30

19-50 600 20 1500-2000 30

50 & above 600-800 20 1500 -2000 30

Pregnancy & Lactation

400-600 20 1500-2000 30

Endocrine society guideline is suitable for Indian Patient to raise the blood level of 25(OH)D consistently above 30 ng/ml


Life Stage group Daily Requirement UL

Infants (0-12 Months) 400 –1000 IU 2000

Adults (1-18 year) 600-1000 IU 4000 IU

Age (19-50 year) 1500-2000 IU 10,000 IU

Age (50 & Above) 1500-2000 IU 10,000 IU

Pregnancy & Lactation (14-18 yr) 600-1000 IU 4000 IU

Pregnancy & Lactation (19-50 yr) 1500 – 2000 IU 10,000 IU

UL:Upper Tolerable intake Level


Dawson-Hughes, Heaney,Holick, Lips,Meunier &Vieth, Osteoporosis Int, 16,713-716,2005

How much Vitamin D Do We Need?“For five of the six authors, the minimum desirable

25(OH)D concentration clusters between 70 and 80 nmol/L.” (28-32 ng/ml)

“This requires~1000 IU/day”


*Down to the bone, Medscape CME, June 2007

+ European Commission Opinion on tolerable upper intake levels of vit D, 2002

Safety of Vitamin D*Doses of 5000-10000

IU/day for 4-5 months have not resulted in elevated serum or urinary calcium levels*

Found to be safeUpper tolerable limit of

intake in adults: 2000 IU/day


Vitamin D & Iron Deficiency:

A

DEADLY DUO


Alien + Predator

Laurel & Hardy

Ideal >30 ng/ml

Acceptable 20-30 ng/ml

Insufficient 10-20 ng/ml

Deficient <10 ng/ml


Indian J Med Res. 2008;127:211-218


Am J Clin Nutr 2000;72:472-5. Am J Clin Nutr 2005;81:1060-4.

Urban Rural60.0%

65.0%

70.0%

75.0%

80.0%

85.0%

≈84% Indian women have 25(OH)D values < 22.5 ng/L.


1. Indian J Med Res. 2011;133:267-273

Deficiency: <15 ng/ml

Insufficiency: 15-20 ng/ml

Severe Deficiency: <5 ng/ml

Vitamin D Deficiency Vitamin D Insufficiency Severe Vitamin D Deficiency0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

Lactating Mothers

Breastfed infants

81.1% 66.7

%

11.6%

19.8%

23.2%

27.1%


J Pediatr Endocrinol Metab. 2009;22(3):241-6.www.ponnitesttubebabycentre.com

Indian J Med Res 2011;133:267-73


Vitamin D Deficiency: Health Implications

Osteomalacia & Rickets

Osteoporosis Diabetes Hypertension & CVD

&

Anemia


Anemia status of Indians India is one of the countries in the world that has

highest prevalence of anemia. (WHO estimates) National Family Health Survey (NFHS-3, 2005)

reveals the prevalence of anemia to be– 24% in adult men.– 70% in pregnant women– 70-80% in children


60-90% Indians have Vitamin D Deficiency

~ 50% of those have anemia

INDIALatitude of 22° 00’N Longitude of 77° 00’W

Prevalence in Pregnant Women & Infants Pregnant women with low serum 25(OH)D levels had

46% higher risk of developing anemia. Am J Clin Nutr. 1992;56:533-536

> 50% infants with Iron Deficiency Anemia had low 25(OH)D levels.

Plos One2010;5(1):e8770


Arch Dis Childhood. 1986;61:843-848

Results significantly different from children with vitamin D ≥10 ng/ml: *p<0-05, **p<0-01.

Vitamin D & Iron Deficiency Link in Toddlers 20% Asian children

had both Vit D Deficiency & Anemia.

Children with Vitamin D deficiency had low Hb and serum iron.


Vitamin D & Iron Deficiency Link in Children

BMJ. 1998;318:28www.ponnitesttubebabycentre.com

Mechanistic Evidence


1. Endocrinology.2006;147(12):5542-5548 2. Ann Hepatol. 2010;89:447-452

Vitamin D Deficiency causes Anemia Possible Mechanism # 1 Vitamin D receptors are present in bone marrow.1 Hematons (buffy coat of bone marrow containing

erythroid precursors) shown to contain high concentration of D25 & 1,25-hydroxyvitamin D.

Thus Vitamin D deficiency could result in reduced activation of erythroid precursors, causing anemia.2


Vitamin D

High local concentrations of 1,25(OH)D in hematopoietic tissues may directly activate erythroid precursors cells in a paracrine fashion.

Vitamin D supplementation will help the initial phase of erythropoesis.

Iron supplementation would be required for the latter phase.


Myelofibrosis was observed in children with Vitamin D deficiency induced rickets.1,2,3

1. J Pediatr. 1989;114:213-217 2. Canad Med Assoc J. 1966;94:395 3. Indian Pediatr. 2005;42:482-484

Vitamin D Deficiency

Reduced activation of Vitamin D receptors in bone marrow

Myelofibrosis

Impaired Erythropoesis

Anemia www.ponnitesttubebabycentre.com

1. Am J Clin Nutr. 1992;56:533-536 2. Proc Soc Exp Biol Med. 1975;149:570-572

(Enterohepatic circulation)

Iron Deficiency Causes Vitamin D Deficiency Background Dietary/supplementary

Vitamin D absorbed from the intestine, is converted to 25(OH)D in the liver.

Some of the 25(OH)D in liver is secreted into bile (mainly as glucuronides) & is reabsrobed by enterohepatic circulation.1,2


Iron Deficiency Anemia

Impaired Epithelial Regeneration & Function

Abnormal GI mucosa

Malabsorption of Fats Pediatrics.1964;33:83-99 www.ponnitesttubebabycentre.com

Malabsorption of Fats

Impairment in Bile secretion

Impaired Vitamin D absorption & 25(OH)D reabsorption in the intestine

Vitamin D Deficiency


Iron deficiency inhibits the metabolism of Vitamin D to 25(OH)D.

Am J Clin Nutr. 1992;56:533-536

IDA Causes Vitamin D Deficiency Possible Mechanism # 2

Clinical evidence > 50% Infants with IDA had decreased concentration of

25(OH)D & 24,25(OH)2D despite receiving daily supplements of Vitamin D.

Treatment with iron increased the concentrations of both iron & vitamin D metabolites.

Increase in serum vitamin D metabolites occurred even when no change was made in the diet or vitamin D supplements.

Clinical Evidence


Study Answers the Crucial QuestionWhy is Vitamin D deficiency disease (rickets)

prevalent in tropical countries (India) with abundant sunlight?

IDA contributes to the high prevalence because the amount of Vitamin D synthesized in the skin is insufficient. Does not satisfy the infants’ requirements.

Moreover, the absorption of vitamin D in the small intestine is limited, due to IDA resulting in the development of rickets.


A combined approach to prophylaxis against iron and vitamin D deficiency should be considered.

Study Snapshot Significant association, not a mere overlap of the two

deficiencies. Children with low Vitamin D concentration had lower

hemoglobin and serum iron concentrations. This was particularly noticeable in winter. 50% of children with

low Vitamin D concentration were anemic compared to none with vitamin D sufficiency.


OR BOTH?


The Never-ending Viscous Cycle leads to……

A Twin EpidemicTo Break the Cycle.......

Supplementation with IRON + VITAMIN D

would provide optimum benefit


Summary

Vitamin D deficiency with Iron Deficiency Anemia is prevalent in Indians of all age groups.

The mechanism of IDA leading to Vitamin D Deficiency or vice versa is not fully established.

The available clinical data indicates a viscous cycle of the twin deficiencies.

Supplementation with 1000 IU Vitamin D + 100 mg Iron daily would synergistically improve the status in Indians.


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