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LH in Human Reproduction (Updated)

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  • There is no need to take notes. I’ve made this lecture available for those willing to review it later. You can find these slides at the website indicated here.
  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • The two-cell system, first proposed by Falck in 1959, is a logical explanation for the events involved in ovarian steroidogenesis. In patients with hypogonadotropic hypogonadism, r-hFSH alone, even when administered continuously and in dose increments of 75UI every 7 days during follicular phase, estradiol production is inadequate despite being adequate to induce follicular growth (as shown by the white dots in the graph). Consequently, endometrium proliferation was also inadequate.
  • It was shown that during the follicular phase, a clear relationship was observed between the dose of rLH and serum estradiol levels.
  • As a consequence, endometrial growth was obtained only if the two higher doses of LH were used. Interestingly, endometrial growth correlated to the estradiol levels up to 75 UI of rLH. No increment was seen by using 225UI of rLH, although serum estradiol levels were twice as high in the 225UI group compared to the 75UI one.
  • In the late stages of follicular development (when the follicle reaches the antral stage), FSH stimulates GCs to express LH receptors. GCs become receptive to LH stimulation.
    To summarize the role of LH in reproductive cycles, it can be said that:
    1 - During the early follicular phase, LH plays a key role in promoting steroidogenesis. Androgens, which are produced in theca cells under LH stimulation, are transferred to GCs and transformed into estrogens via aromatization. Estrogens, in turn, induce uterine changes needed for embryo implantation.
    2 - During the late follicular phase, LH promotes final follicular maturation through direct effects on the follicle.


    In the ovary, granulosa cells are the only target cells of FSH action, whereas both theca and late-stage (In the ovary, granulosa cells are the only target cells of FSH action, whereas both theca and late-stage (luteinizing) granulosa cells contain LH receptors. Increased FSH drive has been shown to be of only limited value in the less gonadotrophin-sensitive ovary, and there is a potential need for LH activity to be part of an individualized treatment regimen tailored for the biologically older ovary.

    FSH receptors are present only on the granulosa cells. LH receptors are present on the theca cells and initially absent on the granulosa cells. In response to LH, theca cells convert cholesterol in androgen (testosterone and androstenedione). Since, CYP17 is located exclusively in thecal cells whereas CYP19 (aromatase) is expressed only in the granulosa. Thus, androgens must diffuse into the granulosa layer to be converted to estrogen via aromatization induced by FSH. Both FSH and LH act via AMPc production. In late follicular phase, FSH induces LH receptor formation on granulosa cells, which acquire LH responsiveness. In granulosa, LH enhances FSH action (increasing estrogen production). At first, estrogens’ levels rise slowly during the late follicular phase. It is then followed by a rapid rise that reaches its peak approximately 24–36 hours prior to ovulation. The LH surge occurs when the peak of estradiol is achieved.
    Most circulating progesterone (~95%) is produced in the intrafollicular compartment by the granulosa cells via the action of 3b-HSD that catalyzes conversion of pregnonolone (delta-4 pathway) under LH influence. The preovulatory rise in progesterone facilitates the positive feedback action of estrogen on the pituitary; the latter is the key factor to induce the midcycle LH peak. Progesterone also stimulates midcycle FSH surge, important to support the full expression of LH receptors in the granulosa layer.

    Ovulation
    The LH surge triggers resumption of oocyte meiosis that had been halted at prophase I (germinal vesicle stage). Also, it promotes luteinization of granulosa cells and synthesis of prostaglandins and other eicosanoids essential for follicle rupture. FSH, LH, and progesterone stimulate the activity of proteolytic enzymes, such as matrix metalloproteinases, disintegrin and metalloproteinase with thrombospondin-like repeats (adamts), which digest collagen in the follicular wall and increase its distensibility [21, 45, 46]. The LH surge also triggers the release of histamine, which has been shown to fully support follicle rupture in some experimental models.
    Granulosa and theca cells also produce plasminogen activator in response to the LH surge, which activates plasminogen in the follicular fluid to produce plasmin. Plasmin, in turn, generates active collagenase that disrupts the follicular wall. After ovulation, the corpus luteum is formed. Hormonal production by luteinized granulosa layer is dependent on the number of LH receptors expressed during the preovulatory phase. Luteal cells derived from the theca compartment continue to produce androgens for aromatization into estrogens by luteal cells derived from the granulosa compartment. In addition, progesterone is produced in both luteinized theca and granulosa cells. As such, the corpus luteum produces estradiol and progesterone under the influence of endogeneous LH activity. As the luteal phase progresses, progesterone inhibits LH release via negative feedback. During the luteal-follicular transition, the LH decline causes the corpus luteum to involute and demise [

  • According to this concept, in the absence of a minimum level of serum LH, E2 production will be insufficient for optimal follicular development and endometrial proliferation. On the other hand, exposure of the developing follicle to excessive LH (beyond a ceiling level) results in atresia and cessation of normal development.
    Evidence suggests that optimal follicular development occurs within an ‘LH window’, above a certain ‘LH threshold’ and below an ‘LH ceiling’.

  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • The general consensus regarding LH is that most women have sufficient levels of endogenous LH and do not require supplementation. However, certain subgroups with low levels of LH may benefit from additional LH.
    Early studies identified a subgroup of normogonadotrophic patients who have normal estimated ovarian reserves but suboptimal responses to FSH stimulation (De Placido et al., 2001, 2004, 2005;
    Mochtar et al., 2007). Such women express ovarian resistance to FSH but seem to be distinct from classical poor responders because some investigators suggest that luteinizing hormone (LH) supplementation improves their ART treatment outcomes (Alviggi et al., 2006).

    The subgroups which may benefit from LH supplementation include women over the age of 35 years, those with a poor response to ovarian stimulation or women with highly suppressed levels of endogenous LH. The general consensus regarding LH is that most women have sufficient levels of endogenous LH and do not require supplementation, although certain subgroups with low levels of LH may benefit from additional LH (Alviggi et al. Reprod Biomed Online 2006;12:221–233; Tarlatzis et al. Hum Reprod 2006;21:90–94; Esteves et al. Reprod Biol Endocrinol 2009;7:111; Marrs et al. Reprod Biomed Online 2004;8:175–182). The subgroups which may benefit from LH supplementation include women over the age of 35 years, those with a poor response to ovarian stimulation or women with highly suppressed levels of endogenous. It has been suggested that a subgroup of women with adequate AFC and FSH levels with hypo-response to ovarian stimulation may also benefit from LH supplementation (Alviggi, et al. RBMOnline 2009). These patients harbor single nucleotide polymorphisms of FSH and LH receptors.

    After pituitary suppression, residual circulating levels of endogenous LH are usually adequate to support multiple follicular growth and oocyte development, also even when drugs containing FSH with low or absent LH activity are administered (Loumaye et al., 1997; Sills et al., 1999). It has been demonstrated that only 1% of LH receptors need to be occupied to drive adequate ovarian steroidogenesis for reproduction. Nevertheless, in a subset of normogonadotrophic patients, the ovarian response to this association is suboptimal.
    It has been suggested that this may be due to a profound suppression of endogenous LH in some women whose activity may fall below an hypothetical threshold value. Thus, it could be hypothesized that those subjects may benefit from the use of LH-containing gonadotrophin preparations (Laml et al., 1999; Fleming et al., 2000; Lèvy et al., 2000; Westergaard et al., 2000; De Placido et al., 2001). Nagawa, 2008: pts with very low LH levels after down-regulation had lower pregnancy and implantaion rates.

    A possible mechanism behind the beneficial effect of exogenous LH supplementation in older women may relate to decreasing numbers of functional LH receptors with increasing age (Vihko et al. 1996). It suggests that younger women, due to a higher number of LH receptors, do not require exogenous LH, while supplementation with exogenous LH in the older woman secures a sufficient LH-induced response. In addition, Piltonen et al. (2003) found that ovarian androgen secretion, i.e. oestrogen precursor secretion capacity, starts to decline as early as before the age of 30 years, again suggesting a diminished capacity of the ovary to respond to LH stimulus with age.

    Another subgroup of women that seems to benefit from exogenous LH supplementation is the group of women with high endogenous LH concentrations on day 8 of stimulation (i.e. >1.99 IU/l). r-hLH supplementation in this subgroup resulted in a significantly higher implantation rate and a marginally higher pregnancy rate (P = 0.07) as compared with the non-supplemented subgroup. This is an interesting and surprising finding. A possible explanation for this phenomenon could be a desensitization of the ovarian LH receptor due to high concentrations of circulating endogenous LH, leading to receptor down-regulation (Zor et al., 1976; Amsterdam et al.. 2002).
     
    LH receptor polymorphism also seems to play a role.

    In summary: less LH receptors, less sensitive LH receptors, Low LH levels.


  • In which we examined the clinical efficacy of different gonadotropin products used for ovarian stimulation in our clinical practice.
    We compared the efficacy of rec-hFSH (n=236), hMG (n=299) and HP-hMG (n=330) in a subset of normogonadotropic down-regulated women undergoing IVF/ICSI. UI (19).
    This difference in favour of r-hFSH was reflected for the amount of gonadotropin used per live birth. To achieve a live birth significantly less r-hFSH was required than hMG (52% reduction) and HP-hMG (21% reduction). One practical implication of this observation is that this marked difference neutralizes part of the cost difference between r-hFSH and hMG preparations. We observed that it was far more common to step the rec-hFSH dose down during ovarian stimulation as compared to hMG.

    We discovered that in our practice, it was far more common to step the rec-hFSH dose down during ovarian stimulation as compared to hMG. The clinicians stated that they felt comfortable with the pen device that allow small dose reductions of 37.5UI , after perceiving a better response with rec-hFSH compared to u-HMG using the same starting doses.
    The clinicians involved in this study stated that they felt comfortable with the pen device, which allowed more precise small dose reductions of 37.5 UI rather the 75UI reductions in the HMG preparations.


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • 22
  • In the late stages of follicular development (when the follicle reaches the antral stage), FSH stimulates GCs to express LH receptors. GCs become receptive to LH stimulation.
    To summarize the role of LH in reproductive cycles, it can be said that:
    1 - During the early follicular phase, LH plays a key role in promoting steroidogenesis. Androgens, which are produced in theca cells under LH stimulation, are transferred to GCs and transformed into estrogens via aromatization. Estrogens, in turn, induce uterine changes needed for embryo implantation.
    2 - During the late follicular phase, LH promotes final follicular maturation through direct effects on the follicle.


    In the ovary, granulosa cells are the only target cells of FSH action, whereas both theca and late-stage (In the ovary, granulosa cells are the only target cells of FSH action, whereas both theca and late-stage (luteinizing) granulosa cells contain LH receptors. Increased FSH drive has been shown to be of only limited value in the less gonadotrophin-sensitive ovary, and there is a potential need for LH activity to be part of an individualized treatment regimen tailored for the biologically older ovary.

    FSH receptors are present only on the granulosa cells. LH receptors are present on the theca cells and initially absent on the granulosa cells. In response to LH, theca cells convert cholesterol in androgen (testosterone and androstenedione). Since, CYP17 is located exclusively in thecal cells whereas CYP19 (aromatase) is expressed only in the granulosa. Thus, androgens must diffuse into the granulosa layer to be converted to estrogen via aromatization induced by FSH. Both FSH and LH act via AMPc production. In late follicular phase, FSH induces LH receptor formation on granulosa cells, which acquire LH responsiveness. In granulosa, LH enhances FSH action (increasing estrogen production). At first, estrogens’ levels rise slowly during the late follicular phase. It is then followed by a rapid rise that reaches its peak approximately 24–36 hours prior to ovulation. The LH surge occurs when the peak of estradiol is achieved.
    Most circulating progesterone (~95%) is produced in the intrafollicular compartment by the granulosa cells via the action of 3b-HSD that catalyzes conversion of pregnonolone (delta-4 pathway) under LH influence. The preovulatory rise in progesterone facilitates the positive feedback action of estrogen on the pituitary; the latter is the key factor to induce the midcycle LH peak. Progesterone also stimulates midcycle FSH surge, important to support the full expression of LH receptors in the granulosa layer.

    Ovulation
    The LH surge triggers resumption of oocyte meiosis that had been halted at prophase I (germinal vesicle stage). Also, it promotes luteinization of granulosa cells and synthesis of prostaglandins and other eicosanoids essential for follicle rupture. FSH, LH, and progesterone stimulate the activity of proteolytic enzymes, such as matrix metalloproteinases, disintegrin and metalloproteinase with thrombospondin-like repeats (adamts), which digest collagen in the follicular wall and increase its distensibility [21, 45, 46]. The LH surge also triggers the release of histamine, which has been shown to fully support follicle rupture in some experimental models.
    Granulosa and theca cells also produce plasminogen activator in response to the LH surge, which activates plasminogen in the follicular fluid to produce plasmin. Plasmin, in turn, generates active collagenase that disrupts the follicular wall. After ovulation, the corpus luteum is formed. Hormonal production by luteinized granulosa layer is dependent on the number of LH receptors expressed during the preovulatory phase. Luteal cells derived from the theca compartment continue to produce androgens for aromatization into estrogens by luteal cells derived from the granulosa compartment. In addition, progesterone is produced in both luteinized theca and granulosa cells. As such, the corpus luteum produces estradiol and progesterone under the influence of endogeneous LH activity. As the luteal phase progresses, progesterone inhibits LH release via negative feedback. During the luteal-follicular transition, the LH decline causes the corpus luteum to involute and demise [


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • A common variant of the β subunit of the LH molecule (v-LH) is identified by an additional sulphonated sugar at asparagine (Asn)-13

    Polymorphism:
    Gene DNA variant existing in the normal population at a frequency of 1% or more

    Mutation:
    Gene DNA variant existing in the normal population at a frequency of less than 1%
  • De Placido et al. studied the effects of LH supplementation in women showing a poor response to ovarian stimulation. ‘Slow responders’ were defined as those who had serum oestradiol levels below 180 pg/ml and no follicles over 10 mm on day 8. These women were randomized to a daily dose of either 75 IU or 150 IU r-hLH. Women classified as ‘good responders’ received no additional r-hLH (control group).
    They found that the high dose of r-hLH was significantly more effective in terms of oocyte development and maturation than the increasing FSH drive. Furthermore, there was no significant difference between the high-dose group and controls in terms of these outcomes.
  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • hCG - α 92 aa - β 145 aa
    8 Glycosylation sites - 37 kDa
    Trophoblastic embryonic cells

    LH - α 92 aa - β 121 aa
    3 Glycosylation sites – 28kDa
    Anterior Pituitary Gland
  • Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) LGR2; HLHR; LCGR; LHR; Lutropin/Choriogonadotropin Receptor; Luteinizing Hormone Receptor:
    Both hormones bind to the same receptor, which is a transmembrane glycoprotein that belongs to the G-protein-coupled receptor superfamily and is present in the ovarian theca cells in females and in the testicular Leydig cells in males (Kessler et al., 1979). Constitutively expressed on theca cells and granulosa cells at a follicle size of 8-12 mm
    LHCGR is found in ovary, testis and extragonodal organs like uterus, that receptor interacts with both luteinizing hormone (LH) and chorionic gonadotropins (such as hCG in humans) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction. LHCGRs are found in the ovary, testis, and many extragonadal tissues. The gene for the LHCGR is found on chromosome 2 p21 in humans, close to the FSH receptor gene. It consists of 70 kbp (versus 54 kpb for the FSHR). The gene is similar to the gene for the FSH receptor and the TSH receptor.The LHCGR consists of 674 amino acids and has a molecular mass of about 85-95 kDA based on the extent of glycolization.

  • Theoretical pathways for the divergence in receptor-mediated signaling between luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Although acting on the same receptor, accumulating evidence suggests that LH binding (A) has a greater impact (thicker arrow) on AKT and extracellular signal-regulated protein kinase (ERK1/2) phosphorylation than hCG does, whereas binding of hCG (B) generates a greater intracellular accumulation (thicker arrow) of cAMP than does LH (Casarini et al., 2012 and Gupta et al., 2012). Pathway components derived from Arey and Lopez (2011). AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; Gs/Gq, G proteins; IP3, inositol triphosphate; LHCGR, luteinizing hormone/choriogonadotropin receptor; PKA, protein kinase A; PLC, phospholipase C; PKC, protein kinase C.
  • Response of human granulosa cells (hGLC) to long-term stimulation with recombinant human luteinizing hormone (r-hLH) or recombinant human chorionic gonadotropin (r-hCG). Intracellular cyclic adenosine monophosphate (cAMP) (bars) and extracellular progesterone (lines) concentrations during chronic exposure to 500 pM r-hLH or 100 pM r-hCG in the presence of a non-selective phosphodiesterase inhibitor (IBMX 500 μM); control cells were not exposed to gonadotropins. Panels illustrate 3 time ranges: (A) 0–12 h; (B) 13–24 h; and (C) 25–36 h. Extracellular accumulation of cAMP continued to increase during the 36-h evaluation period (D). Reproduced with permission from Casarini et al. (2012).
  • 30 IVF/ICSI patients randomized to rFSH or HMG treatment At aspiration granulosa cells collected for gene expression analysis
    Results: 85 genes statistically significantly different in expression
    Results: Expression levels of LH/hCG receptor gene and genes involved in biosynthesis of cholesterol and steroids were expressed at a lower level in HMG-treated granulosa cells
    Conclusion: Preparation used for COS significantly influences the developmental competence of the oocyte and the function of the corpus luteum
  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • I will dedicate the last few minutes of this lecture to explore how we can improve patient care by adapting ovarian stimulation regimens according to biomarkers’ results.


  • In this study from our group, aimed to determine the usefulness of AMH to identify women at risk of excessive and poor response, we studied a group of women undergoing conventional COS for IVF to determine the best cut-off points of AMH.

    ROC analysis revealed that the cutpoints of 2.1 and 0.82 were the best to discriminate excessive and poor-response, with an accuracy of about 90%.


    POOR <=0.82; PPV = 72.5% before and 46.6% after iCOS; p= 0.0280.

    a taxa de cancelamento foi de  22.5% para 10%
     a taxa de nao transferencia por nao ter embriao foi de 40.5% para 28.6%
    a taxa de gravidez clinica por ciclo comecado foi de 21.6% para 25%
    e de gravidez clinica por transferencia foi de 36.3 para 35% (essas todas nao significativas)
  • Then, we used these cutpoints to individualize COS in another group of patients undergoing IVF.
    Mild stimulation using low doses of rec-FSH was given for pts. identified as at risk of excessive response, and rec-hFSH in association with rec-hLH supplementation was given for those identified as at risk of poor response, and in both conditions GnRH antagonists were used.
  • INCLUDE LUVERIS HERE
  • Transcript

    • 1. Sandro Esteves Medical Director, ANDROFERT Campinas, Brazil LH in Human Reproduction Mexico and Panama Lecture Tour 2014
    • 2. http://www.androfert.com.br/review LH in Human Reproduction Mexico 2014 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 June ANDROFERT
    • 3. Learning objectives At the completion of this presentation, participants should be able to: 1. Understand the role of LH in reproductive cycles 2. Identify patient subgroups to whom LH supplementation is beneficial 3. Understand the differences in LH supplementation available gonadotropin preparations ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 June ANDROFERT
    • 4. Is LH important in reproductive cycles? a. Absolutely true b. Maybe true c. False ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 June ANDROFERT
    • 5. 0 9 Endometrium (mm) 0 5 10 15 0 5 10 15 20 Days of Stimulation 50 100 Folliclesize(mm) andFSH(IU/L) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 June ANDROFERT
    • 6. 0 25 75 225 0 500 1000 1500 2000 2500 3000 Day 1 Day 5 Day 10 hCG 0 25 75 225 The European Recombinant Human LH Study Group, JCEM 1998; 83:1507 Rec-hLH administration (IU): ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 June ANDROFERT
    • 7. 0 25 75 225 0 2 4 6 8 Day 1 Day 5 Day 10 hCG 0 25 75 225 rLH The European Recombinant Human LH Study Group, JCEM 1998; 83:1507 Rec-hLH (IU): ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 June ANDROFERT
    • 8. Early follicular phase Steroidogenesis (TC) Late follicular phase Steroidogenesis (TC) Up-regulates FSHr expression (GC) Sustains follicular growth and final follicular maturation (GC) Role of LH in reproductive cycles Physiology ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 June ANDROFERT
    • 9. Balasch & Fábreques 2002 •Adequate androgen and estrogen biosynthesis, normal follicular development and oocyte maturation Normal •Follicular atresia •Premature luteinization •Oocyte development compromised High •Low (and estrogen) synthesis •Impaired follicular maturation •Inadequate endometrial proliferation Low LH Window ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 June ANDROFERT
    • 10. What is the minimum needed LH level? SerumLHUI/L 1.5 1.0 0.5 0.5 Westergaard 2001 0.7 Fleming 1998 1.2 O’Dea 2000 1.35 Mahmoud 2001 Injected rec-hLH LH Cmax 75 UI 0.5 – 1.35 UI/L ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 June ANDROFERT
    • 11. Is LH important in reproductive cycles? a. Absolutely true ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 June ANDROFERT
    • 12. Who need LH supplementation during ovarian stimulation?a. All patients b. Poor responders c. Hypo-responders d. Older women (>35) e. GnRH antagonist protocol ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 June ANDROFERT
    • 13. Natural cycle 5.4 3.1 1.68 0.75 0 1 2 3 4 5 6 SerumLHIU/l Sd1 Sd8 hCG OPU 0.15 GnRH agonist Hypo-hypo GnRH antagonist LH levels in natural and stimulated cycles 1.6 4.8 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 June ANDROFERT
    • 14. Bioactive LH Levels 30-45% have less sensitive ovaries Older patients (≥35 years)3 Poor responders4 Slow/Hypo-responders5 Deeply suppressed endogenous LH levels (hypo-hypo; endometriosis treated with GnRH-a)6 Low 1Tarlatzis et al. Hum Reprod 2006; 2Esteves et al. Reprod Biol Endocrinol 2009; 3Marrs et al. Reprod Biomed Online 2004;4Mochtar MH, Cochrane Database, 2007; 5Alviggi, et al. RBMOnline 2009; 6De Placido et al. Clin Endocrinol (Oxf) 2004 Normal ~55-70% normogonadotropic women undergoing COS1,2 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 June ANDROFERT
    • 15. Among patients treated with FSH and GnRH analogues for in vitro fertilization, is the addition of recombinant LH associated with the probability of live birth? 0.01 0.1 10 100 Study FSH + LH FSH OR (fixed) Weight OR (fixed) n/N n/N 95% CI % 95% CI Agonist Sills 1999 3/13 10/17 10.00 0.21 [0.04, 1.05] Balasch 2001 0/16 1/14 2.32 0.27 [0.01, 7.25] Humaidan 2004 39/116 31/115 31.00 1.37 [0.78, 2.41] Fabregues 2006 24/60 25/60 22.50 0.93 [0.45, 1.93] Tarlatzis 2006 6/55 10/59 12.90 0.60 [0.20, 1.78] Subtotal (95% CI) 72/260 77/265 78.72 0.94 [0.64,1.39] Antagonist Sauer 2004 9/25 10/24 9.80 0.79 [0.25, 2.49] Griesinger 2005 8/62 9/65 11.48 0.92 [0.33, 2.56] Subtotal (95% CI) 17/87 19/89 21.28 0.86 [0.40,1.85] Total (95% CI) 89/347 96/354 100.00 ] advantage r-hFSH Advantage r-hFSH + r-hLH No patient preselection Kolibianakis, et al. Hum Reprod Update 2007;13:445-452
    • 16. Is LH needed in unselected women treated with FSH and GnRH antagonists in IVF? Mochtar et al. 3 RCT (N=216) Baruffi et al. 5 RCT (N= 434) Estradiol on hCG day (pg/ml) WMD 571 (95% CI 259; 882) WMD 514 (95% CI 368; 660) No. retrieved oocytes WMD 0.50 (95% CI -0.68; 1.68) WMD 0.41 (95% CI -0.44; 1.3) CPR†/LBR* †OR 0.79 (95% CI: 0.26; 2.43) †OR 0.89 (95% CI: 0.57; 1.39) Mochtar et al. Cochrane Database Syst Rev. 2007;2:CD005070; Baruffi et al, Reprod Biomed Online. 2007;14:14-25. WMD weight mean difference ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 June ANDROFERT
    • 17. Total Dose per Live Birth (IU)* 0 3,000 7,000 10,000 21.6% Rec-FSHHP-hMG 6,324 7,739 hMG 9,69052.2% *Mean total dose per cycle/Live birth rate (≤35 years) Esteves SC et al. Reprod Biol Endocrinol 2009 N=865; GnRH agonist cycles 30.1 32.4 24.4 rec-FSH HP-HMG HMG LBR (%) p=NS ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 June ANDROFERT
    • 18. Who need LH supplementation during ovarian stimulation? Key points (1) Mandatory in the hypogonadotrophic hypogonadal (HH) patients (FSH and LH<1.2 IU/l) For most women in IVF, endogenous LH levels, irrespective of the GnRH analogue, is sufficient to support follicular development and steroidogenic activity, so «FSH- only« stimulation is enough ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 June ANDROFERT
    • 19. Impaired oocyte quality Decreased fertilization rate Reduced embryo quality Increased miscarriage rates Reduced ovarian paracrine activity Hurwitz & Santoro 2004 Androgen secretory capacity reduced Piltonen et al., 2003 Decreased number of functional LH receptors Vihko et al. 1996 Reduced LH bioactivity Mitchell et al. 1995; Marama et al 1984 3-5 in every 10 treated women have aged ovaries ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 June ANDROFERT
    • 20. 3-5 in every 10 treated women have aged ovaries ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 June ANDROFERT
    • 21. LH supplementation improves clinical pregnancy in women >35 years old ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 June ANDROFERT
    • 22. Fertil Steril 2011 Implantation rate(%) p=0.03 OR: 1.56 (1.04-2.33) p=0.84 OR: 1.03 (0.73-1.47) 27.8 18.9 28.6 26.7 <=35 36-39 FSH+LH FSH ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 June ANDROFERT
    • 23. Bologna Criteria for Poor Responders Ferraretti et al. ESHRE Consensus, Hum Reprod 2011 At least 2 of the following: 1. Advanced maternal age ≥40 years or risk factor for POR 2. Previous POR ≤3 oocytes with conventional stimulation 3. Abnormal ovarian reserve biomarker AFC<5-7; AMH <0.5-1.1ng/mL Or Two episodes of POR after maximal stimulation ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 June ANDROFERT
    • 24. Lehert et al Reprod Biol Endocrinol 2014, 12:17 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 June ANDROFERT Pregnancy rates increased by 30% in poor responders treated with rLH+rFSH
    • 25. Lehert et al 2012 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2014 June ANDROFERT Significant increase of 0.75 oocytes per 1,000 UI gonadotropin administered Lehert et al Reprod Biol Endocrinol 2014, 12:17 rec-hLH improves oocyte yield in Poor Responders
    • 26. Why is LH beneficial in aged women and poor responders? Total Testosterone  55% DHEAS  77% Free Testosterone  49% Androstenedione  64% n = 1423 Davison SL et al JCEM 2005;90:3847 It seems to be a matter of androgens and the anti- apoptotic effect of LH
    • 27. • Action of LH at the follicular level in a dose dependent manner increases androgen production • Androgens are then aromatized to estrogens and help restore the follicular milieu Rationale of LH supplementation (1) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 June ANDROFERT
    • 28. Rationale of LH supplementation (2) Anti-apoptotic effect on granulosa cells Up-regulate growth factors Increase FSH receptor responsiveness Act synergistically with IGF-1 Rimon E et al., 2004; Robinson RS et al., 2007; Tilly JL et al., 1992; Peluso JJ et al., 2001, Ben-Ami I et al., 2009
    • 29. Evidence of a beneficial effect in older women (≥35 yrs.) and poor responders Benefit related to increased androgen production and direct efect on the ovary better follicular recruitment higher number of oocytes better implantation rate Who need LH supplementation during ovarian stimulation? Key points (2) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 June ANDROFERT
    • 30. Definition of hypo-responders (initial poor responders) Alviggi et al. RBM online 2006; 2009 • Normal ovarian reserve • May present follicular growth plateau on D7-D10 • Achieve ‘adequate’ number of oocytes retrieved and estradiol production • But at the expense of an increased cumulative rFSH dose (i.e. >3000 IU) and duration of stimulation ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 June ANDROFERT
    • 31. Why is there a suboptimal response to exogenous FSH in hypo-responders? LH gene polymorphism: V-LHb Carrier frequency 0-52% in various ethnic groups 13 % in Sweden 12-13 % in Denmark and Italy Associated with reduced bioactivity of LH Huhtaniemi et al., 1999; Jiang et al., 1999; Ropelato et al., 1999 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 June ANDROFERT
    • 32. The cumulative FSH consumption is higher in carriers of v-beta LH polymorphism Alviggi et al. Reproductive Biology and Endocrinology, 2013 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 June ANDROFERT
    • 33. Hypo-responders benefit from LH Cochrane review 2007 Mochtar MH, Cochrane Database, 2007 issue 2 Favours r-hFSH Favours r-hFSH + r-hLH Ongoing PR per woman randomized (COS in a GnRH-agonist dow-regulated IVF/ICSI cycle) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 June ANDROFERT
    • 34. 6 9 1110 14 18 22 32 40 FSH step-up (+150 UI) LH supplementation (+150 UI) Normal Responders Mean No. oocytes retrieved IR (%) OPR (%) De Placido et al. Hum Reprod. 2004; 20: 390-6. RCT 260 pts. with “steady” response on stimulation D8 (E2 <180pg/mL; >6 follicles <10mm) LH supplementation in Hypo-responders ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 June ANDROFERT
    • 35. Evidence of a beneficial effect of LH supplementation in hypo-responders (initial poor responders) Dose-related increased LH bioactivity with a positive effect on androgen production and ovarian function Who need LH supplementation during ovarian stimulation? Key points (3) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 June ANDROFERT
    • 36. Who need LH supplementation during ovarian stimulation?a. All patients b. Poor responders c. Hypo-responders d. Older women (>35 yrs.) e. GnRH antagonist protocol ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 June ANDROFERT
    • 37. What product to use for LH supplementation? a. hMG/HP-hMG b. rec-hLH c. Either of the above; they are similar ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 June ANDROFERT
    • 38. Products containing LH Activity Leao & Esteves. Clinics 2014; 69(4): 279–293. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 June ANDROFERT
    • 39. Fertil Steril 2012; 97(3): 561-72 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2014 June ANDROFERT
    • 40. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2014 June ANDROFERT Beta unit Carboxyl terminal segment Longer in hCG Higher receptor affinity in hCG Absent in LH and present in hCG Longer half-life in hCG Sources of LH ActivitySources of LH hCG LH Leao & Esteves. Clinics 2014; 69(4): 279–293.
    • 41. Courtesy of Xuliang Jiang Sharing the same α subunit and 81% of the aminoacid residues of the β subunit, LH and hCG bind to the same receptor LH/hCG receptors: • Constitutively expressed on theca cells • Expressed on granulosa cells at a follicle size of 8- 12 mm ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2014 June ANDROFERT
    • 42. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2014 June ANDROFERT Divergence in receptor-mediated signaling between LH and hCG Choi & Smitz Mol Cell Endocrinol 2014; 383(1-2):203–13.
    • 43. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2014 June ANDROFERT Casarini et al PloS One 2012;7:e46682
    • 44. Half-life in serum and differential downstream effects of r-hLH and r-hCG binding to LHCGR. Cell type r-hLH r-hCG Half-life t1/2α<comma> range of mean<comma> hrs 0.6–1.3a<comma>b 3.9–5.5c t1/2β<comma> range of mean<comma> hrs 9–12a<comma>b 23–31c Response ED50 (pM) COS-7/LHCGRe 530.0 ± 51.2 107.1 ± 14.3 Time to maximal cAMP accumulationd COS-7/LHCGRe 10 min 1 h ERK1/2 activationf hGLC Strong Weak AKT activationf hGLC Strong Minimal Neuregulin 1 inhibition in presence of ERK1/2 and AKT pathway blockade hGLC Abrogated Unaffected CYP19A1 expression in presence of ERK1/2 pathway blockade hGLC Increased Unaffected
    • 45. …LH and hCG downstream cascade pathways are different LH hCG LHR and FSHR expression (Trafficking of retinoic acid : RXRB, TTR, ALDH8A1) Meiosis and follicular maturation (TRA : RXRB, TTR, ALDH8A1; IL11; AKT3) Follicular development (IL11; AKT3) Cellular growth (RXRB, TTR, ALDH8A1; IL11;AKT3) Ovarian stereodogenesis (TRA : RXRB, TTR, ALDH8A1) Embryo development & survival (AKT3) Aromatase inhibition (PPARS) Apoptosis enhancement (DNAsi) LH hCG Grondal ML et al. Fertil Steril 2009; Menon KM et al. Biol Reprod 2004;; Ruvolo et al. Fertil Steril 2007
    • 46. 19 14 14 31 26 25 0 5 10 15 20 25 30 35 Fixed 2:1 r-hFSH (150IU)/r-hLH (75IU) HMG rec-hFSH + HMG Duration of Stimulation (days) Mean No. oocytes retrieved IR (%) CPR per transfer (%) Buhler KF, Fisher R. Gynecol Endocrinol 2011 Matched case-control study; N=4,719 IVF pts. P=0.02 Does it matter whether hMG hCG (hMG) or rec-hLH? ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2014 June ANDROFERT
    • 47. • RCT comparing rec-hFSH + rec-hLH (2:1) vs. HP-hMG • Higher No. oocytes retrieved in the rFSH + rLH (2:1) group (9.8 vs 7.3; p<0.01) • 2/3 of the patients in rFSH+rLH group (vs. 1/3 hMG group) had frozen embryos to transfer if fresh transfer failed Fábregues F et al. Gynecol Endocrinol. 2013 May;29(5):430-5. Does it matter whether hMG hCG (hMG) or rec-hLH? ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2014 June ANDROFERT
    • 48. Significant differences exist between LH and hCG at boh the molecular and functional level Preliminary evidence indicates that the choice of products containing LH activity impact IVF clinical outcome What product to use for LH supplementation? Key points ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2014 June ANDROFERT
    • 49. What product to use for LH supplementation? a. hMG/HP-hMG b. rec-hLH c. Either of the above; they are similar ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2014 June ANDROFERT
    • 50. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2014 June ANDROFERT How we use LH supplementation at Androfert
    • 51. Ovarian stimulation protocol ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2014 June ANDROFERT
    • 52. iCOS at Androfert Dosage based on clinical profile and AMH/AFC  Morning injections  rec-hFSH 112.5-150 IU high responders  rec-hFSH 187.5-225 IU normal responders  rec-hFSH+rec-hLH (2:1 ratio) poor/hypo-responders; women ≥35 yrs. • Antagonist regimen  Daily evening injections  Flexible protocol (when follicle reaches 12-14mm)  Last injection day of trigger (morning) Individualization of COS Androfert ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2014 June ANDROFERT
    • 53. • Monitoring: TVUS + E2 days 1; 6; 9-10 • Ovulation trigger not before stimulation D9 Trigger when 2-3 follicles =>17 mm Rec-hCG or GnRH-agonist (triptorelin 0.2mg SC) No (FSH/LH) stimulation on triggering day Freeze all in GnRH-a cycles • Oocyte pick-up: 35h post-trigger • LPS early pregnancy (9-12 weeks) Transdermal estradiol + vaginal progesterone gel (90mg) Individualization of COS Androfert ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2014 June ANDROFERT
    • 54. Population Cut-off Sensitivity Specificity Accuracy AMH* ng/m L High- responder1 2.1 85% 79% 0.82 Poor responder2 0.82 76% 86% 0.88 *Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16 Biomarkers of ovarian response AMH ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2014 June ANDROFERT
    • 55. Rec-hFSH + rec-hLH (2:1 ratio) from stimulation D1 Total dose: 300 IU FSH + 150 IU LH GnRH antagonist (flexible): mean diameter 13mm LH trigger with rec-hCG (mean diameter 17-18 mm) Our Preferred Stimulation Regimen in Expected Poor Responders 2 3 4 5 76 8 9 10 111 Menses 12 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2014 June ANDROFERT
    • 56. Individualized vs. Conventional COS in Expected Poor Responders (N=118) 72.0 3.5 45.0 20.0 46.6 4.8 23.3 26.8 0 20 40 60 80 Observed Poor Response (%) Oocytes retrieved (N) Cancellation (%) Pregnancy/cycle (%) cCOS (Long GnRH with recFSH) iCOS (GnRH Antag. with rFSH+rLH) Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved; Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16. *p<0.05 * * * ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2014 June ANDROFERT
    • 57. GnRH antagonist flexible protocol Rec-hFSH + rec-hLH (2:1 or 3:1 ratio) from D1 Total dose: 150-225 IU FSH + 75 IU LH How tse LH in Coin SLH supplementation in women ≥35 years and hypo-responders (normal ovarian biomarkers) 2 3 4 5 76 8 9 10 111 Menses 12 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2014 June ANDROFERT
    • 58. LH in Human Reproduction Conclusions Adequate LH levels critical for steroidogenesis, follicular development and oocyte maturation Androgen secretory capacity decreases with ovarian aging Mechanisms include decreased number of functional LH receptors and ovarian paracrine activity. LHr polymorphisms involved in hypo-responders ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2014 June ANDROFERT
    • 59. Many patients will benefit from LH supplementation during COS: Poor/hypo responders Age >35 years; hypo-hypo Sources are rec-hLH and hMG LH and hCG differ at molecular, functional and clinical levels iCOS with rec-hLH is one of our strategies to maximize pregnancy in IVF LH in Human Reproduction Conclusions ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2014 June ANDROFERT
    • 60. ThankYou gracias

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