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Blood serum and follicular fluid relaxin: a pilot study of the hormone effects on ovarian function and fertilization efficiency

December 2020
Journal of obstetrics and women s diseases 69(5):59-68

DOI:10.17816/JOWD69559-68

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CC BY 4.0

Authors:

Olesya N Bespalova

Research Institute of Obstetrics and Gynecology named after D.O. Ott

Valeria A. Zagaynova

Research Institute of Obstetrics and Gynecology named after D.O. Ott

Olga Pachuliia

Research Institute of Obstetrics and Gynecology named after D.O. Ott

Alexander M. Gzgzyan

Research Institute of Obstetrics and Gynecology named after D.O. Ott

Show all 11 authorsHide

Hypothesis/aims of study. To date, one of the most important avenues of research in the field of reproductive medicine is the searching for new biochemical markers of oocyte quality and the prediction of the effectiveness of in vitro fertilization (IVF) protocols. The aim of this study was to assess the effect of relaxin levels in blood serum and follicular fluid on the efficiency of ovulation stimulation, fertilization, and characteristics of the embryos. Study design, materials and methods. This prospective randomized cohort study included 11 patients undergoing infertility treatment in a superovulation stimulation protocol using gonadotropin-releasing hormone antagonists. Age, body mass index, hormonal status, ovarian response, endometrial thickness and structure, the number and quality of oocytes and embryos, as well as fertilization efficiency were assessed. The level of relaxin in blood serum and follicular fluid samples was determined on the day of transvaginal follicle puncture using enzyme immunoassay. Results. A correlation between follicular fluid relaxin levels and body mass index, age, the number of oocytes, and their fertilization efficiency (p 0.05) was established. Changes in follicular fluid relaxin level were revealed depending on the gonadotropin preparations (p 0.05) and triggers of final maturation of oocytes (p 0.05). The tendency of the effect of gonadotropin doses on circulating relaxin levels, and of the hormone itself on endometrial thickness and the quality of oocytes was determined. Conclusion. Determination of the relaxin concentration can be considered as a promising method for predicting the result of ovarian stimulation and the efficiency of fertilization in IVF protocols.

Available via license: CC BY 4.0

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ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES 59

 618.177-089.888.11-07:618.112.2

DOI: https://doi.org/10.17816/JOWD69559-68

РЕЛАКСИН СЫВОРОТКИ КРОВИ И ФОЛЛИКУЛЯРНОЙ ЖИДКОСТИ:

ПИЛОТНОЕ ИССЛЕДОВАНИЕ ВЛИЯНИЯ ГОРМОНА НА ФУНКЦИЮ ЯИЧНИКОВ

И ЭФФЕКТИВНОСТЬ ОПЛОДОТВОРЕНИЯ

©О.Н. Беспалова1, В.А. Загайнова1, О.В. Косякова1, А.М. Гзгзян1, 2, И.Ю. Коган1, 2, Ю.П. Милютина1,

Н.Н. Ткаченко1, В.Л. Бородина1, Е.А. Лесик1, И.Д. Мекина1, Е.А. Комарова1

1      «- 

,   . .. », -;

2       

«-  », -

Для цитирования: Беспалова О.Н., Загайнова В.А., Косякова О.В., Гзгзян А.М., Коган И.Ю., Милютина Ю.П., Ткаченко Н.Н.,

Бородина В.Л., Лесик Е.А., Мекина И.Д., Комарова Е.А. Релаксин сыворотки крови и фолликулярной жидкости: пилотное

исследование влияния гормона на функцию яичников и эффективность оплодотворения // Журнал акушерства и женских

болезней. – 2020. – Т. 69. – № 5. – С. 59–68. https://doi.org/10.17816/JOWD69559-68

Поступила: 10.08.2020 Одобрена: 15.09.2020 Принята: 12.10.2020

 Актуальность.         -

         -

 .

Цель—          

 , ,   .

Материалы иметоды исследования.     

11,         -

 --.  ,   ,  , -

 ,   ,   , , 

.         

      .

Результаты исследования.       

  , ,  ,    (p < 0,05).  

         -

 (p < 0,05),      (p < 0,05).     -

      —     .

Выводы.         

   ,    -

 .

 Ключевые слова: ;  ;  ; ; -

 ; .

BLOOD SERUM AND FOLLICULAR FLUID RELAXIN:

A PILOT STUDY OF THE HORMONE EFFECTS ON OVARIAN FUNCTION

AND FERTILIZATION EFFICIENCY

©O.N. Bespalova1, V.A. Zagaynova1, O.V. Kosyakova1, A.M. Gzgzyan1, 2, I.Yu. Kogan1, 2, Yu.P. Milyutina1,

N.N. Tkachenko1, V.L. Borodina1, E.A. Lesik1, I.D. Mekina1, E.A. Komarova1

1 The Research Institute of Obstetrics, Gynecology, and Reproductology named after D.O. Ott,” Saint Petersburg, Russia;

2 Saint Petersburg State University, Saint Petersburg, Russia

For citation: Bespalova ON, Zagaynova VA, Kosyakova OV, Gzgzyan AM, Kogan IYu, Milyutina YuP, Tkachenko NN, Borodina VL,

Lesik EA, Mekina ID, Komarova EA. Blood serum and follicular fluid relaxin: A pilot study of the hormone effects on ovarian function

and fertilization efficiency. Journal of Obstetrics and Women’s Diseases. 2020;69(5):59-68. https://doi.org/10.17816/JOWD69559-68

Received: August 10, 2020 Revised: September 15, 2020 Accepted: October 12, 2020

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES

Введение

   -

     -

    -

   

 ,   

,   -

 ,  

invitro,    

 [1, 2].    -

   -

   

     -

  (),  

 ,   -

 ,   

    [3].

      -

   

    ,

      

   

    -

  () [4].

     37-

 ,   

, ,  -

   ,  ,

 , , -

, , , -

 . [5, 6].

   

   — -

   

   5–6, -

    

   .   -

   , 

   -

, — -2 [7].  

    

,  - ,

     

  [8].  

  ,   -

    [9]. ,

  (relaxin/insulin-like family

peptide receptor 1 — RXFP1) 

     

  [10]. In vitro 

RXFP1  RXFP2    

 ,    -

  (   -

,    ),  

   

  ,  -

   , 

  in vitro [11–13].

    -

    -

   [14].    -

   

    [15].

     

    -

   . ,

 ,  

  , 

800 /    

   -

 ,  <200/— -

  [16].

 Hypothesis/aims of study. To date, one of the most important avenues of research in the field of reproductive medicine

is the searching for new biochemical markers of oocyte quality and the prediction of the effectiveness of in vitro fertiliza-

tion (IVF) protocols. The aim of this study was to assess the effect of relaxin levels in blood serum and follicular fluid

on the efficiency of ovulation stimulation, fertilization, and characteristics of the embryos.

Study design, materials and methods. This prospective randomized cohort study included 11 patients undergoing

infertility treatment in a superovulation stimulation protocol using gonadotropin-releasing hormone antagonists. Age,

body mass index, hormonal status, ovarian response, endometrial thickness and structure, the number and quality of

oocytes and embryos, as well as fertilization efficiency were assessed. The level of relaxin in blood serum and follicular

fluid samples was determined on the day of transvaginal follicle puncture using enzyme immunoassay.

Results. A correlation between follicular fluid relaxin levels and body mass index, age, the number of oocytes, andtheir

fertilization efficiency (p < 0.05) was established. Changes in follicular fluid relaxin level were revealed depending on the

gonadotropin preparations (p < 0.05) and triggers of final maturation of oocytes (p < 0.05). The tendency of the effect

of gonadotropin doses on circulating relaxin levels, and of the hormone itself on endometrial thickness and the quality

of oocytes was determined.

Conclusion. Determination of the relaxin concentration can be considered as a promising method for predicting the

result of ovarian stimulation and the efficiency of fertilization in IVF protocols.

 Keywords: relaxin; in vitro fertilization; follicular fluid; oocyte; fertilization efficiency; endometrium.

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES 61

,   -

   , 

 ,  .

 ,   -

    -

    

,   -

    .

Цель исследования —  

     

  ,   

 ,   -

 ,    

    

 .

Материалы и методы

   -

    -

    (n = 9), -

,    

 (n = 1)    

 (n = 1),   

  

«  . ..». 

11     

:    20  43,

   

   (  -

    « 

...»).     -

    ,

   ,  

 ()>35/2,  -

 ,  , 

 ,  

1-  2- ,  -

  .

Стимуляция овуляции

     -

     -

.   

 3-     -

    -

 (--, +-

, Merck Serono, ; Merck Se-

rono, )   -

  (-,

IBSA Institut Biochimique, S.A., ),

 ---

 () (   0,25 , Vetter

Pharma, Organon, ).  

    

 , , , 

   .

    -

   .  

   -

   

  250 (Merck Serono, )

   —    0,2

(Ipsen Pharma Biotech, ): n = 7  n = 4

.

   -

    (-

  , ), -

   (, ).

   

.   -

    

   , 

 >17.  

 ()    

    -

 36   .

    -

  , 

   -

 ().   .

    -

     -

      -

    (MII)

 .   

   -

      -

      

 .   -

     -

    

      -

MII  .  -

  5-    Vitrolife ().

   5  

 D.K. Gardner (Gardner D.K., 1999).

    -

 ≥3BB.    -

    5-  -

.    

   

   .

Получение образцов сыворотки крови

и аспирация фолликулярной жидкости

     -

    -

   ,  

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES

 .  -

   20 -

 1500g.   

    -

 (    , 

  ). 

   1500 g  

20.    -

 1–2.  –80 °  

.

Определение уровня релаксина в сыворотке

крови и фолликулярной жидкости

   

   

    -

-2 - 

   

[SED868Hu ELISA Kit for Relaxin 2 (RLN2), ].

   -

 3,1–500/.   -

   -

      .

Статистический анализ

    

  Statistica 10 (StatSoft,

Inc.).   

   – .  -

   

   – 

   – .  -

    [25-; 75- -

].    

   ,

   -

   

     

,    

.    (а),

   

   -

   (-

,   , -

 ,     

 ).  -

   . 

    . 

    -

 .    

   -

    rs.

     -

:  — 0–0,3, — 0,3–0,5,

— 0,5–0,7, — 0,7–0,9,  -

— 0,9–1.  р < 0,05  

  .

Результаты исследования

   -

     -

 (n = 11),   -

    .

   -

 (n = 1),    -

   -

 (n = 1),    (n = 5)

    -

     

   

 . , 

   -

  ,    .

    -

    

    -

 (r = –0,65),  (r = –0,67), 

  (r = 0,66)  -

  (r = 0,62),  

    

(r = –0,85).   

    

 .  

   

,     -

,  ,  

  ,  

 (.1).

  

   , -

  /+,  -

  ,  

(Z = 2,279; p < 0,05).   

    -

    -

   . 

    

    -

 (.2, a)

   -

      

    -

 .    -

     -

    

(Z = –2,051, p < 0,05) (.2, b).

     -

  .    

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES 63

    (а = 0,96), -

 (а = –0,87),   (а = 0,99), 

(а = –0,87),    (а = 0,99),

  

(а = 0,99)   (а = 1), 

  (а = –0,99).

     -

   (а = 0,9), 

0,01

0,03

0,05

0,11

–0,14

0,18

0,22

–0,29

–0,45

0,56

–0,57

0,71

–0,9

Высокая корреляционная сила связи (0,7–0,9) / High correlaon strength (0.7–0.9)

Средняя корреляционная сила связи (0,5–0,7) / Average correlaon strength (0.5–0.7)

Слабая корреляционная сила связи (0,3–0,5) / Weak correlaon strength (0.3–0.5)

Очень слабая корреляционная сила связи (0–0,3) / Very weak correlaon strength (0–0,3)

Релаксин сыворотки крови / Blood serum relaxin

–0,7 –0,5 –0,3 –0,10,1 0,30,5 0,70,9

–0,9 –0,7 –0,5 –0,3 –0,10,1 0,30,5 0,70,9

Индекс массы тела

Body mass index

Возраст

Age

Лютеинизирующий гормон

Luteinizing hormone

Эффективность оплодотворения

ооцитов / Oocyte ferlizaon eﬃciency

Количество эмбрионов

Number of embryos

Антимюллеров гормон

An-Müllerian hormone

Количество бластоцист

Number of blastocysts

Фолликулостимулирующий гормон

Follicle smulang hormone

Количество ооцитов

Obtain oocytes count

Количество фолликулов

Follicles count

Толщина эндометрия

Endometrial thickness

Суммарная доза гонадотропинов

Total dose of gonadotropins

Качество ооцитов

Oocyte quality

Релаксин фолликулярной жидкости / Follicular ﬂuid relaxin

Индекс массы тела

Body mass index

Возраст

Age

Лютеинизирующий гормон

Luteinizing hormone

Эффективность оплодотворения

ооцитов / Oocyte ferlizaon eﬃciency

Количество эмбрионов

Number of embryos

Антимюллеров гормон

An-Müllerian hormone

Количество бластоцист

Number of blastocysts

Фолликулостимулирующий гормон

Follicle smulang hormone

Количество ооцитов

Obtain oocytes count

Количество фолликулов

Follicles count

Толщина эндометрия

Endometrial thickness

Суммарная доза гонадотропинов

Total dose of gonadotropins

Качество ооцитов

Oocyte quality

0,09

–0,1

–0,14

–0,16

0,21

0,53

0,54

0,6

0,62*

–0,65*

0,66*

–0,67*

–0,81*

Рис. 1.         

 (* p < 0,05)

Fig. 1. Correlation between blood serum and follicular fluid relaxin levels and the studied parameters (* p < 0.05)

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES

  (а = 0,84), 

 (а = 0,99),  

(а = 0,99),   

 5-   (а = 0,99; а = 0,99), -

    

(а = –0,89)   -

 (а = –0,88) (.3).

     

    ,

   , -

  ,  

 .    -

    -

    

   -

  .

120,0аb

рФСГ

rFSH

Релаксин, пг/мл / Relaxin, pg / ml

чМГТ

hMGT

рФСГ

rFSH

Сыворотка

Blood serum

Фолликулярная жидкость

Follicular ﬂuid

Сыворотка

Blood serum

Фолликулярная жидкость

Follicular ﬂuid

чМГТ

hMGT

100,0

80,0

60,0

40,0

20,0

0,0

120,0

Овитрель

Ovitrelle

Релаксин, пг/мл / Relaxin, pg / ml

Диферелин

Diphereline

Овитрель

Ovitrelle

Диферелин

Diphereline

100,0

80,0

60,0

40,0

20,0

0,0

Рис. 2.          -

      (a);     

         -

   (b) (* p < 0,05)

Fig. 2. a. Blood serum and follicular fluid relaxin levels with the use of gonadotropin preparations in the study groups;

b.Blood serum and follicular fluid relaxin levels with the use of triggers of final oocyte maturation in the study groups (* p < 0.05)

Метод вращения: варимакс с нормализацией

Varimax rotaon with the Keiser normalizaon

Метод отбора: анализ главных компонент

Principal Component Analysis

ассоциировано с фактором 1

related to Factor 1

ассоциировано с фактором

related to Factor 2

Фактор 1 / Factor 1

Фактор 2 / Factor 2

0,60,40,20,0–0,2–0,4–0,6–0,8–1,0–1,2

–1,0

–0,8

–0,6

–0,4

–0,2

0,0

0,2

0,4

0,6

0,8

1,0

1,2

0,81,0

116

15 11

Рис. 3.    

  : , 

 1: 2 —   -

 , 3— , 4—  -

    , 7 —  

, 9—   , 10— 

 , 12—  -

, 14 —  ; -

,    2: 1 —  

  , 5 —  -

    , 6 —  -

    ,

8 —   , 11 — 

 , 13—  , 15— 

  5- , 16 —  

   5- 

Fig. 3. Two-dimensional graph of factorial loads of the

studied indicators. Graph numbering: indicators associ-

ated with Factor 1: 2, follicular fluid relaxin level; 3, age;

4, blood serum anti-Müllerian hormone level; 7, body

mass index; 9, day of puncture; 10, number of punctured

follicles; 12, number of oocytes; 14, fertilization efficiency;

indicators associated with Factor 2: 1, blood serum relaxin

level; 5, blood serum luteinizing hormone level; 6, blood

serum follicle-stimulating hormone level; 8, ∑ dose of

gonadotropins; 11, endometrial thickness; 13, quality of

oocytes ; 15, number of blastocysts on day 5; 16, number

of good quality embryos on day 5

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES 65

Обсуждение

    -

   

   

       -

,     

    -

 - [8, 17].  -

    -

     

 , , , 

   

    .

  in vitro  -

      

 [18, 19].  

    ,

  , -

    [20].  

   

     -

   -

 ,    -

  . ,

     -

  ,

   -

     , 

   . ,  -

    

   -

   ,  

,   -

[17].     -

    

      [21].

  

   -

      

.  , -

 in vitro,   -

    -

, ,   

    -

 .   

    -

     

 .      

  ,   -

.    

   

    -

,     

 .

   

   , 

 .    

     -

      .

   

     -

,    -

   

    

    ( -

  ,   

 ,   ) [22].

   -

   

   ,  

  ,  ,

   

 .     -

   

    -

     

 [23, 24].

    ,  -

     -

      -

    . ,

   , 

    

  

(-, ) ,   -

 (),    

 .     

   -

    ,  

   -

  .   -

     -

   

:     -

    . ,

   -

   .

   

 ,  ,

    ,  -

    -

     

 .

  LGR-7 

   -

 ,    

RXFP1.    

   ,

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES

     ,

      [25].

   -

   (, -1

   -

),      -

  [9, 26].  

   -

   (vascular endothelial growth

factor — VEGF)   

 ,   

 .  in vitro , 

    

    ,

  

      -

   , 

  , 

 ,   

  [27, 28].

Выводы

    -

    

    -

    -

  ,   

,   .

   

    ,

 ,  ,

.   

    

    

  .

Дополнительная информация

Конфликт интересов.   

  .

Финансирование.  

     558-2019-

0011 «  -

    -

     -

  » 

 Protocol Registration and Results System

ClinicalTrials.gov, ID NCT04458454.

Вклад авторов

О.Н. Беспалова—   -

.

В.А. Загайнова, Е.А. Лесик, Е.А. Комарова—

 .

Н.Н. Ткаченко, В.Л. Бородина— 

  .

В.А. Загайнова—  .

Ю.П. Милютина—  -

 .

В.А. Загайнова, О.В. Косякова, И.Д. Мекина—

 .

О.Н. Беспалова, А.М. Гзгзян, И.Ю. Коган —

 .

Литература

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oocyte maturation and quality: Signaling pathways, regula-

tion, and clinical impact. Reprod Sci. 2020;27(6):1223-1252.

https://doi.org/10.1007/s43032-019-00137-x.

2. Tong J, Sheng S, Sun Y, et al. Melatonin levels in follicular

fluid as markers for IVF outcomes and predicting ovarian

reserve. Reproduction. 2017;153(4):443-451. https://doi.

org/10.1530/REP-16-0641.

3. Sun Z, Wu H, Lian F, et al. Human follicular fluid metabo-

lomics study of follicular development and oocyte qua-

lity. Chromatographia. 2017;80(6):901-909. https://doi.

org/10.1007/s10337-017-3290-6.

4. Hussein MH, Al-Khafaji QA, Mufedah AJ, et al. Evaluation of

lipids in serum and follicular fluid on oocyte and human em-

bryo quality after ICSI. Iraqi Journal of Embryo and Inferti-

lity Researches. 2017;7(1):52-61. https://doi.org/10.28969/

ijeir.v7.r7.

5. Poulsen LC, Pla I, Sanchez A, et al. Progressive changes

in human follicular fluid composition over the course of

ovulation: Quantitative proteomic analyses. Mol Cell Endo-

crinol. 2019;495:110522. https://doi.org/10.1016/j.mce.

2019.110522.

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Том Вып уск

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org/10.1095/biolreprod.104.030585.

Информация об авторах (Information about the authors)

Олеся Николаевна Беспалова— - . ,  -

   .  «  . ..», -

. https://orcid.org/0000-0002-6542-5953. SPIN-: 4732-

8089. E-mail: shiggerra@mail.ru.

Olesya N. Bespalova— MD, PhD, DSci (Medicine), Deputy Director

for Research. The Research Institute of Obstetrics, Gynecology,

andReproductology named after D.O.Ott, Saint Petersburg, Russia.

https://orcid.org/0000-0002-6542-5953. SPIN-code: 4732-8089.

E-mail: shiggerra@mail.ru.

Валерия Алексеевна Загайнова—   -

  .  « 

...», -. https://orcid.org/0000-0001-6971-

7024. SPIN-: 7409-4944. E-mail: zagaynovav.al.52@mail.ru.

Valeria A. Zagaynova— MD, Post-Graduate Student. The Assisted

Reproduction Technology Department, the Research Institute of

Obstetrics, Gynecology, and Reproductology named after D.O.Ott,

SaintPetersburg, Russia. https://orcid.org/0000-0001-6971-7024.

SPIN-code: 7409-4944. E-mail: zagaynovav.al.52@mail.ru.

ISSN 1684-0461 (Print)

ISSN 1683-9366 (Online)

Журнал акушерства и женских болезней

Journal of Obstetrics and Women’s Diseases

Том Вып уск

2020

Volume

Issue

  / ORIGINAL RESEARCHES

Информация об авторах (Information about the authors)

Ольга Владимировна Косякова—   

 1.  «  . .. », -

. E-mail: for.olga.kosyakova@gmail.com.

Olga V. Kosyakova— MD, Post-Graduate Student. The Department

of Pathology of Pregnancy No. 1, the Research Institute of Obstetrics,

Gynecology, and Reproductology named after D.O.Ott, Saint

Petersburg, Russia. E-mail: for.olga.kosyakova@gmail.com.

Александр Мкртичевич Гзгзян— - . , 

 ,   

 .  «  . ..»,

-;   , 

  .   «-

  », -.

https://orcid.org/0000-0003-3917-9493. E-mail: ovrt@ott.ru.

Alexander M. Gzgzyan— MD, PhD, DSci (Medicine), Head of the

Department of Reproductology, Head of the Assisted Reproduction

Technology Department. The Research Institute of Obstetrics,

Gynecology, and Reproductology named after D.O.Ott, Saint

Petersburg, Russia; Professor. The Department of Obstetrics,

Gynecology, and Reproductive Sciences, the Faculty of Medicine,

SaintPetersburg State University, Saint Petersburg, Russia.

https://orcid.org/0000-0003-3917-9493. E-mail: ovrt@ott.ru.

Игорь Юрьевич Коган— - . , , -. ,

  «  . ..», -;

  ,  

 .   «-

 », -. https://orcid.

org/0000-0002-7351-6900. SPIN-: 6572-6450. Scopus Author ID:

56895765600. E-mail: ovrt@ott.ru.

Igor Yu. Kogan— MD, PhD, DSci (Medicine), Professor, Corresponding

Member of RAS, Director. The Research Institute of Obstetrics,

Gynecology, and Reproductology named after D.O. Ott, Saint

Petersburg, Russia; Professor. The Department of Obstetrics,

Gynecology, and Reproductive Sciences, the Faculty of Medicine,

SaintPetersburg State University, Saint Petersburg, Russia. https://orcid.

org/0000-0002-7351-6900. SPIN-code: 6572-6450. Scopus Author ID:

56895765600. E-mail: ovrt@ott.ru.

Юлия Павловна Милютина— . . , 

  .  «  . .. »,

-. https://orcid.org /0000-0003-1951-8312.

E-mail: milyutina1010@mail.ru.

Yulia P. Milyutina— PhD, Chairman of the Council of Young Scientists.

The Research Institute of Obstetrics, Gynecology, and Reproductology

named after D.O.Ott, Saint Petersburg, Russia. https://orcid.org /0000-

0003-1951-8312. E-mail: milyutina1010@mail.ru.

Наталия Николаевна Ткаченко— . . , 

 .  «  . ..»,

-. https://orcid.org/0000-0001-6189-3488.

E-mail: iagmail@ott.ru.

Natalia N. Tkachenko— PhD, Head of the Laboratory of Endocrinology.

The Research Institute of Obstetrics, Gynecology, and Reproductology

named after D.O.Ott, Saint Petersburg, Russia. https://orcid.org/0000-

0001-6189-3488. E-mail: iagmail@ott.ru.

Валентина Леонидовна Бородина— - 

.  «  . ..», -

. E-mail: iagmail@ott.ru.

Valentina L. Borodina— Laboratory Assistant. The Laboratory of

Endocrinology. The Research Institute of Obstetrics, Gynecology,

andReproductology named after D.O.Ott, Saint Petersburg, Russia.

E-mail: iagmail@ott.ru.

Елена Александровна Лесик— . . ,  

   ,  -

   .  

«-  », -

. https//orcid.org/0000-0003-1611-6318. E-mail: ovrt@ott.ru.

Elena A. Lesik— PhD, Senior Researcher. The Laboratory of Early

Embryogenesis; Embryologist. The Assisted Reproduction Technology

Department, Saint Petersburg State University, SaintPetersburg, Russia.

https//orcid.org/0000-0003-1611-6318. E-mail: ovrt@ott.ru.

Ирина Дмитриевна Мекина— . . ,  

   ,  -

    .

 «-  »,

-. https://orcid.org/0000-0002-0813-5845.

E-mail: ovrt@ott.ru.

Irina D. Mekina— PhD, Senior Researcher. The Laboratory of Early

Embryogenesis; Senior Embryologist. The Assisted Reproduction

Technology Department, Saint Petersburg State University,

SaintPetersburg, Russia. https://orcid.org/0000-0002-0813-5845.

E-mail: ovrt@ott.ru.

Евгения Михайловна Комарова— . . , 

  ,   -

  .   «-

  », -.

https://orcid.org/0000-0002-9988-9879. E-mail: ovrt@ott.ru.

Evgenia M. Komarova— PhD, Head of the Laboratory of Early

Embryogenesis, Embryologist. The Assisted Reproduction Technology

Department, Saint Petersburg State University, SaintPetersburg, Russia.

https://orcid.org/0000-0002-9988-9879. E-mail: ovrt@ott.ru.

Transcriptomic responses to cytotoxic drug cisplatin in water flea Daphnia magna

Article

Aug 2022
ENVIRON TOXICOL PHAR

Cytotoxic drugs have been recognized by the European Union as the potential threat in the aquatic environment. As a typical cytotoxic drug, effects of long-term exposure to cisplatin at the environmentally relevant concentrations on the crustacean health and its molecular mechanism remain undetermined. In this study, the growth and reproduction of Daphnia magna resulting from cisplatin exposure were initially assessed. While the phenotypes were not altered in 2 μg L⁻¹, 20 μg L⁻¹, and 200 μg L⁻¹ treatment groups, cisplatin at 500 µg L⁻¹ significantly reduced the offspring number to 8-13 neonates in each brood, which was lower than 13-27 neonates in the control group. In addition to the delay in the time of first pregnancy, the body length was decreased by approximate 12.13% at day 7. Meanwhile, all daphnids died after exposure to 500 µg L⁻¹ cisplatin for 17 days. Transcriptome profiling bioassays were performed for 10 days to explore the alternation at the molecular level. Briefly, 980 (257 up- and 723 down-regulated), 429 (182 up- and 247 down-regulated) and 1984 (616 up-regulated and 1368 down-regulated) genes were differentially expressed (adj p < 0.05) in low (2 μg L⁻¹), medium (200 μg L⁻¹) and high (500 μg L⁻¹) cisplatin treatment groups, respectively. Differentially expressed genes were primarily enriched in the digestion and absorption, nerve conduction, endocrine interference, and circulatory related pathways. Specifically, the down-regulated digestive secretion and nutrient absorption and neuronal conduction pathways may lead to insufficient energy supply involved in growth and reproduction, and hinder ovarian development and cell growth. Down-regulation of ovarian steroids and relaxin signaling pathways may be related to the reduction of offspring number and delayed pregnancy, and reduced body length of D. magna may attribute to the enrichment of insulin secretion pathway. In addition, the death of D. magna may result from the reduced expression of genes in cardiomyocyte contraction and apoptosome processes. Taken together, this study revealed the potential toxic mechanism of cisplatin in a model water flea.

Biological profile of the follicular fluid. A pilot study

Article

Jul 2023

BACKGROUND: One of the most important research areas in the field of reproductive medicine is the search for biochemical and immunological parameters of oocyte quality and predicting the effectiveness of assisted reproductive technology protocols. AIM: The aim of this study was to evaluate the expression of follicular fluid soluble human leukocyte antigen-G, human leukocyte antigen-E, human leukocyte antigen-C, progesterone-inducing blocking factor, and relaxin levels in women with reproductive disorders. MATERIALS AND METHODS: This prospective cohort study included 22 patients undergoing infertility treatment in a superovulation stimulation protocol using gonadotropin-releasing hormone antagonists. The inclusion criteria were age from 25 to 39 years, tubal-peritoneal factor infertility, and voluntary participation informed consent. The levels of soluble human leukocyte antigen-G, human leukocyte antigen-E, human leukocyte antigen-C, progesterone-inducing blocking factor, and relaxin in follicular fluid samples were determined on the day of transvaginal follicle puncture by enzyme immunoassay. RESULTS: We established an inverse correlation between the expression levels of progesterone-inducing blocking factor and relaxin (r = 0.450) in the follicular fluid, antibodies to thyroperoxidase (r = 0.649), and thyroid-stimulating hormone (r = 0.519). We also found a direct correlation between human leukocyte antigen-E parameters in the follicular fluid, age (r = 0.813) and Body Mass Index (r = 0.866), as well as between human leukocyte antigen-C expression levels and total testosterone (r = 0.960). No data were obtained on any significant correlations between the studied biomarkers and the number of received oocytes. CONCLUSIONS: In this comprehensive study, we were the first who found the expression levels of five different follicular fluid components, namely, soluble human leukocyte antigen-G, human leukocyte antigen-E, human leukocyte antigen-C, progesterone-inducing blocking factor, and relaxin. Such a complex assessment of the follicular fluid can allow for establishing the quality of the oocyte to predict the onset of pregnancy in an in vitro fertilization protocol.

Evaluation of Lipids in Serum and Follicular Fluid on Oocyte and Human Embryo Quality after ICSI

Article

Full-text available

Jan 2017

Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Article

Full-text available

Jan 2020
REPROD SCI

The ovarian follicle luteinizing hormone (LH) signaling molecules that regulate oocyte meiotic maturation have recently been identified. The LH signal reduces preovulatory follicle cyclic nucleotide levels which releases oocytes from the first meiotic arrest. In the ovarian follicle, the LH signal reduces cyclic nucleotide levels via the CNP/NPR2 system, the EGF/EGF receptor network, and follicle/oocyte gap junctions. In the oocyte, reduced cyclic nucleotide levels activate the maturation promoting factor (MPF). The activated MPF induces chromosome segregation and completion of the first and second meiotic divisions. The purpose of this paper is to present an overview of the current understanding of human LH signaling regulation of oocyte meiotic maturation by identifying and integrating the human studies on this topic. We found 89 human studies in the literature that identified 24 LH follicle/oocyte signaling proteins. These studies show that human oocyte meiotic maturation is regulated by the same proteins that regulate animal oocyte meiotic maturation. We also found that these LH signaling pathway molecules regulate human oocyte quality and subsequent embryo quality. Remarkably, in vitro maturation (IVM) prematuration culture (PMC) protocols that manipulate the LH signaling pathway improve human oocyte quality of cultured human oocytes. This knowledge has improved clinical human IVM efficiency which may become a routine alternative ART for some infertile patients.

Human Follicular Fluid Metabolomics Study of Follicular Development and Oocyte Quality

Article

Full-text available

Jun 2017
CHROMATOGRAPHIA

The granulosa cells are tightly connected with the oocyte in oocyte-corona-cumulus complex. There is bidirectional signal regulation and material transport between granulosa cells and oocyte such as steroid hormone biosynthesis, oocyte gene transcription and protein synthesis regulation. The follicular fluid was of the secretion of ovarian granulosa cells and the diffusion of serum. It contains a variety of bioactive molecules for the oocyte growth and development. These molecules transport and biosynthesis plays a very important role in regulating meiosis, hormone synthesis and follicle and oocyte maturation and development. Thus, the altered levels of molecules in follicular fluid were closely associated with follicular development and oocyte quality. The follicular fluid is an optimal source for non-invasive biochemical predictor to evaluate the follicular development and the oocyte quality, because it is the only biological fluid in which the oocyte develops. This study aims to understand what happened in the process of oocyte aging and evaluate the oocyte quality with the growth of the age. Therefore, follicular fluid was obtained from 22 healthy younger (23–28 years old) and 22 older (35–46 years old) women undergoing intracytoplasmic sperm injection (ICSI) due to male factor. The follicular fluid samples were analyzed by ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF). Based on principal component analysis, the samples were clustered into two different regions. Fifteen differences endogenous metabolites were found and identified as 4,5-dihydroorotic acid, maleylacetoacetic acid, 4-oxo-retinoic acid, rhazidiqenine Nb-oxide, nicotine glucuronide, deoxycorticosterone, LysoPC (14:0), LysoPC (16:0), LysoPC (18:0), phytosphingosine, phosphatidylcholine (16:0/22:0), 3-hydroxynonanoyl carnitine, DG(14:1(9Z)/22:2(13Z,16Z)/0:0), 5,6-dihydrouridine and TG(18:1(11Z)/24:0/20:5(5Z,8Z,11Z,14Z,17Z)) from the two groups using UPLC-TOF. These results described the relationship of female reproductive dysfunction with oocyte metabolism disorder including energy metabolism, cell proliferation and apoptosis and abnormal oxidation. These changes may have an adverse effect on oocyte development, maturation, fertilization and subsequent embryo development.

EFFECT OF OOCYTES QUALITY AND OVARIAN RESERVE ON THE THERAPEUTIC POTENTIAL OF IN VITRO FERTILIZATION IN PATIENTS OF LATE REPRODUCTIVE AGE

Article

Full-text available

Feb 2016

The paper discusses the interference of the quality of oocytes and ovarian reserve status in the therapeutic potential of in vitro fertilization in women of late reproductive age. It was substantiated that the age factor decreased both female fertility and possibility of the successful fertilization.

Progressive changes in human follicular fluid composition over the course of ovulation: Quantitative proteomic analyses

Article

Jul 2019
MOL CELL ENDOCRINOL

Follicular fluid (FF) acts as a vehicle for paracrine signalling between somatic cells of the follicle and the oocyte. To investigate changes in the protein composition of FF during ovulation, we conducted a prospective cohort study including 25 women undergoing fertility treatment. Follicular fluid was aspirated either before or 12, 17, 32 or 36 h after induction of ovulation (five patients per time point). Liquid chromatography-mass spectrometry was used to identify and quantify FF proteins. In total, 400 proteins were identified and the levels of 40 proteins changed significantly across ovulation, evaluated by analysis of covariance (adjusted p < 0.05) and on-off expression patterns. The majority peaked after 12-17 h, e.g., AREG (p < 0.0001), TNFAIP6 (p < 0.0001), and LDHB (p = 0.0316), while some increased to peak after 36 h e.g., ACPP (p < 0.0001), TIMP1 (p < 0.0001) and SERPINE1 (p = 0.0002). Collectively, this study highlights proteins and pathways of importance for ovulation and oocyte competence in humans.

Understanding relaxin signalling at the cellular level

Article

Dec 2018
MOL CELL ENDOCRINOL

The peptide hormone relaxin mediates many biological actions including anti-fibrotic, vasodilatory, angiogenic, anti-inflammatory, anti-apoptotic, and organ protective effects across a range of tissues. At the cellular level, relaxin binds to the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) to activate a variety of downstream signal transduction pathways. This signalling cascade is complex and also varies in diverse cellular backgrounds. Moreover, RXFP1 signalling shows crosstalk with other receptors to mediate some of its physiological functions. This review summarises known signalling pathways induced by acute versus chronic treatment with relaxin across a range of cell types, it describes RXFP1 crosstalk with other receptors, signalling pathways activated by other ligands targeting RXFP1, and it also outlines physiological relevance of RXFP1 signalling outputs. Comprehensive understanding of the mechanism of relaxin actions in fibrosis, vasodilation, as well as organ protection, will further support relaxin's clinical potential.

Effect of Mode of Conception on Maternal Serum Relaxin, Creatinine, and Sodium Concentrations in an Infertile Population

Article

Jun 2018

Objective: To investigate how the mode of conception affects maternal relaxin, creatinine, and electrolyte concentrations. Background: Pregnancies achieved by fertility treatment often begin in a nonphysiologic endocrine milieu with no corpus luteum (CL) or with many corpora lutea. The CL produces not only estradiol and progesterone but is also the sole source of relaxin in early pregnancy, a hormone that may contribute to maternal systemic and renal vasodilation. There is limited data about maternal physiology in early pregnancy during fertility treatment, and studies have rarely considered the potential effect of the absence of the CL. To begin to address this gap in knowledge, we sought to investigate how the mode of conception affects maternal relaxin, creatinine, and electrolyte concentrations. Methods: One hundred eighty-four women who received care at an academic infertility practice provided serum samples. Levels of relaxin 2, creatinine, and electrolytes were compared between 4 groups defined on the basis of mode of conception which corresponded to categories of CL number: (1) absence of the CL, (2) single CL, (3) multiple CL from ovarian stimulation not including in vitro fertilization (IVF), and (4) multiple CL from IVF with fresh embryo transfer. Results: Relaxin-2 levels were undetectable in patients lacking a CL. Creatinine, sodium, and total CO2 levels were significantly higher in the 0 CL group (relaxin absent) compared to all other groups (relaxin present). Compared to clomiphene, use of letrozole was associated with a lower relaxin level. Conclusion: Early creatinine and sodium concentrations are increased in the absence of relaxin. Given the increasing utilization of frozen embryo transfer, further studies comparing programmed with natural cycles are warranted.

Follicular fluid cytokine composition and oocyte quality of polycystic ovary syndrome patients with metabolic syndrome undergoing in vitro fertilization

Article

Jan 2017
CYTOKINE

Purpose: To provide insights into the correlation among lipid metabolism, cytokine profiles in the follicular fluid (FF) and embryo quality of women with Polycystic Ovary Syndrome (PCOS) with metabolic syndrome (MS). Methods: Ninety women undergoing in vitro fertilization (IVF) treatment were recruited, including 60 PCOS patients (PCOS non MS and PCOS MS) and 30 age-matched controls. Individual FF samples were analyzed using the cytometric multiplex immunoassay. Results: In the FF, the PCOS MS group was associated with higher, total cholesterol (TC), triglyceride (TG) and lower high-density lipoprotein (HDL) concentrations compared with that in the control group (P<0.05). The FF tumor necrosis factor-α (TNF-α) level in the PCOS MS group was 3.89±1.18ng/mL, which was significantly higher compared with the control (2.94±1.02ng/mL) and PCOS non-MS groups (3.05±1.21ng/mL) (P=0.002), while the granulocyte colony-stimulating factor (G-CSF) level in the PCOS MS group (4.18±1.33ng/mL) was lower compared with the control (5.61±1.82ng/mL) and PCOS non-MS groups (5.32±1.91ng/mL) (P=0.004). The FF G-CSF showed a trend toward negative relationship with TG and TC; TNF-α concentration was positively associated with TG. The percentage of top-quality embryo decreased in the PCOS MS group than in the other two groups (20% vs. 38.4% and 34.6%). Conclusions: In conclusion, there was an elevated lipolysis condition within the FF of PCOS MS patients and the TNF-α and G-CSF levels in FF were associated with top-quality embryo percentage. TNF-α and G-CSF may be the key cytokines involved in the mechanism of decreased embryo development potential in PCOS MS patients.

Melatonin levels in follicular fluid as markers for IVF outcomes and predicting ovarian reserve

Article

Jan 2017

Good-quality oocytes are critical for the success of in vitro fertilization (IVF), but, to date, there is no marker of ovarian reserve available that can accurately predict oocyte quality. Melatonin exerts its antioxidant actions as a strong radical scavenger that might affect oocyte quality directly, since it is the most potent antioxidant in follicular fluid. To investigate the precise role of endogenous melatonin in IVF outcomes, we recruited 61 women undergoing treatment cycles of IVF or intracytoplasmic sperm injection (ICSI) procedures and classified them into three groups according to their response to ovarian stimulation. Follicular fluid was collected to assess melatonin levels using a direct RIA method. We found good correlations between melatonin levels in follicular fluid with age, anti-Müllerian hormone (AMH), and baseline follicle-stimulating hormone (bFSH), all of which have been used to predict ovarian reserve. Furthermore, melatonin levels correlated to IVF outcomes, higher numbers of oocytes were collected from patients with higher melatonin levels as did the number of oocytes fertilized, zygotes cleaved, top quality embryos on D3, blastocysts obtained, and embryos suitable for transplantation. The blastocyst rate increased in concert with the melatonin levels across the gradient between the poor response group and the high response group. These results demonstrated that the melatonin levels in follicular fluid are associated with both the quantity and quality of oocytes and can predict IVF outcomes as well except they are highly relevant biochemical markers of ovarian reserve.

The Role of Relaxin in Normal and Abnormal Uterine Function During the Menstrual Cycle and Early Pregnancy

Article

Jun 2016

The hormone relaxin is a 6-kDa peptide with high structural similarity to insulin. It is primarily produced by the corpus luteum during pregnancy but is also synthesized by other reproductive organs such as the uterus, decidua, and placenta. Relaxin binds to its receptor RXFP1, which has been localized to a wide variety of reproductive and nonreproductive tissues. The peptide’s many uterotropic effects include stimulating uterine growth and vascularization, remodeling extracellular matrix components, and regulating vascular endothelial growth factor in preparation for implantation. Evidence also supports a role for relaxin in the systemic maternal vascular adaptations required for a healthy pregnancy. Diminished relaxin levels in early pregnancy are linked with increased risks of miscarriage and the development of preeclampsia. In addition to pregnancy, relaxin may also play a functional role in the uterus during the menstrual cycle, and modified relaxin activity may contribute to gynecological disorders such as uterine fibrosis and endometriosis. Despite over 75 years of research, we still have a limited understanding of relaxin’s broad roles in the uterus, particularly as there are significant species differences in its synthesis and activity, which restricts the use of animal models for human-centric questions. Here, we review current knowledge regarding relaxin actions in the human uterus during the menstrual cycle and in early pregnancy, with a focus on its potential roles in various gynecological disorders, as well as the pregnancy disorders such as preeclampsia, recurrent miscarriage, and early pregnancy loss.

Blood serum and follicular fluid relaxin: a pilot study of the hormone effects on ovarian function and fertilization efficiency

Abstract

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