INFERTILITY Assessment and treatment of patients with fertility problems Dr Nitu Raje-Ghatge.
Infertility Treatment in India | Best Fertility Specialist
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GREETINGS FROM
PONNI HOSPITAL
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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
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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
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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
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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
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Obese people are more likely to be vitamin D deficient and vitaminD deficiency seems to predispose people to obesity
People living at higher latitudes
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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
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• Inflammatory bowel disease• Celiac disease• Cystic fibrosis• Pancreatic insufficiency
Complete clothing coverage Malabsorption
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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
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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.
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How prevalent is Vit D deficiency in India ?
Prevalence varying from 50-100%INDIA
Latitude of 22° 00’N Longitude of 77° 00’W
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Why does this happen?Changing lifestylesDress codeUrban- less sun exposureRural- less calcium intakeAvoiding the sunSunscreensDark skin
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Why in India?
Two problems:Color of our skinUnfortified dairy products
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Vitamin D & calcium metabolism
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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
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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.
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Vitamin-D Deficiency: Bone What are the problems in india
In adults: osteomalacia Mainly symptoms
In growing children: rickets Mainly signs
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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]
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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
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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
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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.
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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.
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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.
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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
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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
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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
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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
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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”
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*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
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Vitamin D & Iron Deficiency:
A
DEADLY DUO
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Alien + Predator
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Laurel & Hardy
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Ideal >30 ng/ml
Acceptable 20-30 ng/ml
Insufficient 10-20 ng/ml
Deficient <10 ng/ml
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Indian J Med Res. 2008;127:211-218
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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.
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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%
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J Pediatr Endocrinol Metab. 2009;22(3):241-6.www.ponnitesttubebabycentre.com
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Indian J Med Res 2011;133:267-73
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Vitamin D Deficiency: Health Implications
Osteomalacia & Rickets
Osteoporosis Diabetes Hypertension & CVD
&
Anemia
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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
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60-90% Indians have Vitamin D Deficiency
~ 50% of those have anemia
INDIALatitude of 22° 00’N Longitude of 77° 00’W
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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
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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.
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Vitamin D & Iron Deficiency Link in Children
BMJ. 1998;318:28www.ponnitesttubebabycentre.com
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Mechanistic Evidence
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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
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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.
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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
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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
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Iron Deficiency Anemia
Impaired Epithelial Regeneration & Function
Abnormal GI mucosa
Malabsorption of Fats Pediatrics.1964;33:83-99 www.ponnitesttubebabycentre.com
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Malabsorption of Fats
Impairment in Bile secretion
Impaired Vitamin D absorption & 25(OH)D reabsorption in the intestine
Vitamin D Deficiency
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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.
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Clinical Evidence
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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.
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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.
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OR BOTH?
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The Never-ending Viscous Cycle leads to……
A Twin EpidemicTo Break the Cycle.......
Supplementation with IRON + VITAMIN D
would provide optimum benefit
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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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