Latent hyperprolactinemiaand infertility

Salt Lake City, USAJuly 11th, 2012

Maciej Barczentewicz, Radoslaw Maksym, Oksana Furman, Elzbieta Rydz

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My BriefSubjective

„NaPro History”

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2004

Tekst

http://www.popepaulvi.com/

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Cracow, Poland 2007

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Warsaw Poland 2007

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Galway, Ireland 2008

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Lublin, Poland 2008

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Lublin, Poland 2009

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Belarussia 2009

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Khazakistan 2009

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Bioethical Comitee Orthodox Patriarchate

Moscow, Russia 2010

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Poznań, Poland 2010

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Lviv, Ucraine 2011

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GALWAY, IRELAND FCCE 2012

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Latent hyperprolactinemiaand infertility

Salt Lake City, USAJuly 11th, 2012

Maciej Barczentewicz, Radoslaw Maksym, Oksana Furman, Elzbieta Rydz

Presentation outline:• Prolactin

• Regulation of prolactin

• Action of prolactin

• Symptoms of hyperprolactinemia

• Causes of hyperprolactinemia

• Measurement of prolactine level

• Concept of latent hyperprolactinemia

• Management

• Our results

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Prolactin (PRL):• Polypeptide hormone, 198 amino acids

• Weakly homologous to GH and hPL

• Short circulating half-life ~20-50 minutes

• Normal serum levels:

– ♀ 10-25 ng/mL (µg/L)

– ♂ 10-20 ng/mL (µg/L)

• Forms:

– Small 21,5 kDa

– Big 50kDa

– Big-big >100kDa

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Macroprolactinemia

Regulation of PRL:• Pulsatile secretion

• Circadian rhythm

• Highest secretion during REM dream (in the morning)

• Induced by

Stress

Exercises

Meals

Breast stimulation

Sexual intercourse

Drugs

Pregnancy and breastfeeding

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Regulation of PRL:• Secreted mainly by lactotropes (20% anterior pituitary)

• Unique regulation among pituitary hormones:

predominant control is inhibition by dopamine (D2)

- permanent inhibition ensures low PRL basal level

- peaks are result of disinhibition rather than stimulation

• Stimulated by:

- TRH – primary hypothyroidism is common cause of

hyperprolactinemia

- VIP Vasoactive Intestine Peptide

- Estrogens – cause lactotrope hyperplasia

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Action of PRL:• Proliferation of lobuloalveolar epithelium in breast

• Maintains lactation

• Inhibition of GnRH pacemaker in hypothalamus:

- suppress sexual drive

- decrease fertility

• Influence:

- brain function

- immune response

- electrolyte balance (Ca2+)

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Symptoms of hyperprolactinemia:• GnRH pacemaker dysfunction

• Inhibition of FSH & LH secretion

• Dysfunctional growth of ovarian follicles

• Luteal phase deficiency

• Amenorrhoea or oligomenorrhoea

• Anovulation

• Galactorrhoea

• Decrease of libido and dyspareunia

• PMS

• Osteoporosis

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Causes of hyperprolactinemia:• Disruption of hypothalamo-pituitary axis

• Pituitary adenoma (Prolactinoma)

• Ectopic PRL secretion (tumours, myoma)

• Primary hypothyroidism, Addison disease and Cushing disease

• Severe renal failure

• Drugs:

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-Neuroleptics-Antidepressants-Antiemetic-Antihistaminica-Estrogens-Opiats-and many more...

Measurement of PRL level:•On empty stomach

•After rest, in comfort

•Between 6:00-8:00 AM

- One of most commonly assessed hormones in infertility.

~30% of infertile women suffer from hyperprolactinemia!!!

-Up to 20% of women suffer from galactorrhoea with „normal” basal PRL level during their life-time. Estman (1990) Diagnostic Endocrinology

Single measurement gives poor insight into real biological effect in a given patient, due to:

- stress peaks

- nocturnal peaks

- short half-life time

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Measurement of PRL:• 24h serial measurement

• Dynamic tests – potential secretory activity

-Direct – drugs stimulating PRL secretion

TRH, L-dopa, nomifensine, verapamil

-Indirect – drugs abrogating inhibition

Metoclopramide (MCT), domperidone

• MCT dynamic test:

-60 minutes after 10mg MCT p.o.

-MCT/basal level ratio is calculated

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MTC dynamic test:Dynamic tests are generaly not recommended by Endocrine

Society guidelines (Melmed 2011).

MCT indirect stimulation dynamic test:

Is used in Poland in the borderline cases: widely by endocrinologists but rarely by Ob&Gyn (Zgliczynski 2005)

Was not mentioned in the guidelines.

-Metoclopramide is a selective D2 receptor

blocker that reduce action of dopamine on

hypophysis

-Thus MCT is useful to reveal

intrinsic potential of PRL secretion

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Modified from:

Zgliczyński et al 2005

& Polish Endocrine Society Guidelines

Concept of latent hyperprolactinemia:There is poorly described group of subfertile patients with

– Normal basal PRL level

– Pathologically increased PRL in MCT dynamic test (>600% of basal level)

– Excluded hypothyroidism (TSH,fT3, fT4 = WNL )

Latent hyperprolactinemia was described and studied by:

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- Mühlenstedt D et al. (1977) Prolactin and short luteal phase infertility. Fertil Steril 28:373- Schenker GJ (1992) Stress and human reproduction. In: Klimek R (ed) Pre- and perinatal psycho-medicine.- Kostal M et al (1997) The influence of latent hyperprolactinaemia on the levels of LH, FSH, E2 and T in the midfollicular phase of the cycle, Arch Gynecol Obstet 259: 65–68

Kostal et al 1997

Concept of latent hyperprolactinemia:

There is poorly described group of subfertile patients with

– Normal basal PRL level

– Pathologically increased PRL in MCT dynamic test (>600% of basal level)

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Concept of latent hyperprolactinemia:

Functional hyperprolactinemia is similar condition with:

– Mildly increased basal PRL level

– Pathologically increased PRL in MCT dynamic test (>600% of basal level)

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Concept of latent hyperprolactinemia:During routine examination PRL levels are low, because latent

hyperprolactinemia is veiled by high dopaminergic inhibition.

Predisposition to high PRL secretion results in massive PRL surges (incidents) caused by physiological triggers.

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Those incidents of hyperprolactinemia exerts biological role and cause subfertility.

>>Treatment by dopaminergic agonist, that causes permanent D2 repression, level the PRL

bursts and is beneficial for patient fertility.

Patients and methods:All infertile women treated at clinic are routinely

assessed by:

- Basal PRL level

- PRL level in MTC dynamic test

- TSH, fT3, fT4 levels

- Careful manual breast examination that includes observation ofmammary secretion. Bottom of nipple is pressed gently to check for any discharge.

- Other standard NPT hormonal examination

For presented study patients were also examined with psychological questionnaires standardized for stress assessment: PSS-10 and COPE. Questionnaires were also

performed on randomized group of patients.

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Breast anatomy

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Breast examination for nipple secretion

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Nipple secretion/ discharge

Milky Serous

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Nipple secretion/ discharge

Green Milky Black/Brown

Management:Patients recognized as a cases of latent or functional

hyperprolactinemia were treated with raising doses of bromocriptine (starting from 1,25mg/24h, t1/2=3,3h)

Final dose was precisely adjusted under control of:

– Basal PRL <25ng/ml

– MCT test <600%

Although low doses of bromocriptine were well tolerated in case of adverse effect other D2 agonists can be used:

– Qinagolide – t1/2=22h, 75-300ug/24h

– Cabergoline – t1/2=66h, 0,5-3mg/7d

– Pergolide, lizuride …

– Vitex Castus Agnus??? (D2 agonist)

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Management:What states in Cochrane Database?

Only 3 trials with 127 women with unexplained subfertility

MCT dynamic test were NOT performed!!!

There are no proves for administration bromocriptine in all patients with unexplained subfertility

(odds ratio = 1.12, 95% confidence interval: 0.48 to 2.57).

Bromocriptine for unexplained subfertility in women.

Hughes et al. (2007)

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Chart change after bromocriptine medication

Our results:

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Our results:

The mean age at the moment of diagnosis in the latent hyperprolactinemia group was 32,9 (25-38).

The mean efforts to conceive time before diagnosis was 2,98 year (10 months – 13 years).

Mean bromocriptine treatment interval was 71 daysand the treatment was ceased by positive pregnancy test confirmed by TV-USG.

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Our results:

The mean basal prolactin level was 19,9 ng/ml and the mean MCT level was 1140% of the basal level.

Majority of latent hyperprolactinemia patients (60%) presented breast secretion at careful breast examination.

In latent hyperprolactinemia group occurrence of breast secretion positively correlated with basal level of prolactin in Spearman Rank Correlation test (R=0,784, p=0,0072).

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Our results:

All patients but one were diagnosed and treated elsewhere before.

The previous (mis-)diagnosis includes: male factor, adhesions, Fallopian tube occlusion, uterine septum, uterus arcuatus, idiopathic infertility, secondary infertility, PCOS.

Two patients underwent unsuccessful IVF and three of them underwent unsuccessful IUI (one donor semen insemination) before admission to Clinic.

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Our results:The PSS10 test showed statistically insignificant trend of

higher stress intensity among latent hyperprolactinemia group comparing to control subjects.

No differences were found among groups in the strategies of dealing with stressful conditions.

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CASE PRESENTATION

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Couple 1 G-0 P-0

Age of wife: 39 Age of husband: 45

• Efforts to conceive: 14 years

• Diagnosis on entry into NPT : primary infertility, LPS 2000; adhesions, fallopian tubes occluded (HSG 2006), toxoplasmosis; FSH 15,8

• male factor : ch Hashimoto from 1997 ; sperm analysis: 9mln sperm count, 2% motility, morph? unknown

• IUI 3x

• IVF 1x 2005: 5 embryos, 3 transferred, 1 frozen

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Couple 1 G-0 P-0CrMS from : 13.07.2009

NPT diagnosis: HUSBAND

• Multiple food intolerance including dairy milk, poultry egg, wheat, candidiasis of alimentary track,

Treatment

• exclusion diet, antifungal treatment flukonazole 50mg for 21 days

• Co-enzyme Q 10, l-karnityne, (sperm suplements)

• pycnogenol, levothyroxine, selenium (Hashimoto thyroiditis)

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Couple 1 G-0 P-0CrMS from : 13.07.2009

NPT diagnosis: WIFE

• Cyst on left ovary

• FSH 13,0

• Latent hyperprolactinemiaPRL 12 ng/ml 200 ng/ml after MTC

• Limited mucus MCS 6.9

• Low progesterone at Peak+7

• treatment with bromocryptine, progesterone, vitamin B6

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Couple 1 G-0 P-0

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Couple 1 G-0 P-0

Control Sperm analysis: 68 mln sperm, 59% motility, 62% morphology

• Natural conception in the 9th cycle observed

• Pregnancy test HCG (+) positive

• Ultrasound confirms presence of embryo

• CRL 9w1d FHR (+)

• Progesterone at 6th week of gestation: 56,1 ng/l

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Couple 1 G-0 P-0

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Baby girl 3410 g born October 21st 2010 Caesarian Section

Couple 1 G-0 P-0

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CASE PRESENTATION

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Couple nr 2 G-0 P-0Woman age 36 Man age 33

Infertility 2 years

Diagnosis on commencement of treatment:

male infertility, sperm sample 2009:

sperm count 2mln per ml /motility A 0% B 8%

sperm normal morphology 1%,

leucocytes:3.9mln/ml

Earlier clinical interventions:

5 x IUI with donor sperm

IVF 2009, transfer of 3 embryos

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Couple nr 2 G-0 P-0

CrMS from: 18.08.2010

• Diagnosis in NPT: HUSBAND

Sperm microculture: Staphyloccus KO (-) –treatment with doxocyclinum 0.1g 20 days, ciprofloxacine 20 days

• sperm sample after treatment

6mln sperm, 8% mobility, 1%morphology, elevated viscosity

• treatment: tamoxifen, undestor, Coenzyme Q 10, l-carnitine, pycnogenol, acetylcysteine

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Couple nr 2 G-0 P-0CrMS from: 18.08.2010

NPT Diagnosis: WIFE

• Latent hyperprolactinemiaFasting PRL 24ng/ml

389ng/ml after 10 mg MCT

• treatment bromocriptine 1.25 mg at bedtime

• Low progesterone at Peak+7 (no measurement of progesterone levels – diagnosis based on TEBB on the Creighton chart)

• treatment progesterone 2x100 mg vaginal tablets

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Couple nr 2 G-0 P-0

• Sperm analysis: 14 mln sperm, 19% motility, 17% morph, culture negative

• Natural conception in the second observed cycle

• Pregnancy test HCG (+) positive

• Ultrasound confirms presence of fetus

• GS 6w6d CRL 6w4d FHR (+)

• Progesterone at 6 weeks: 115 nmol/l

• EDD 17.06.2011

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Couple 2 G-0 P-0

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Couple 2 G-0 P-0

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Couple 2 G-0 P-0

Baby girl 3670 g born June 8th 2011 Caesarian Section

Take home messages:

>>Single PRL measurement poorly represents effect of PRL in a given patient.

>>Metoclopramide (MCT) dynamic test is a useful tool to estimate induced PRL secretion that suggest individual PRL secretion response to stimulus.

>>Patient with normal basal level of PRL and abnormal rise in MCT test:

– often present symptoms of hyperprolactinemia

– can benefit from dopaminergic agonist treatment.

>>Further studies are warranted on the group of subfertile women with high PRL secretion predisposition .

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Correspondence address:Maciej BarczentewiczLeśna 3720-423 Lublin,POLAND

phone: 0048 667 660 289e-mail: maciej.barczentewicz@infertility.pl