Nathalie Massin

Lack of Androgen Receptor Expression in Sertoli Cells Accounts for the Absence of Anti-Mullerian Hormone Repression during Early Human Testis Development

CONTEXTnPuberty is associated with increased testicular testosterone (TT) synthesis, which is required to trigger spermatogenesis and to repress anti-Mullerian hormone (AMH) production. However, testicular gonadotropin stimulation during fetal and newborn life neither initiates spermatogenesis nor represses AMH.nnnOBJECTIVEnWe postulated that a lack of androgen receptor (AR) expression in Sertoli cells (SC) might explain why these processes do not occur during early human development.nnnMETHODS AND PATIENTSnUsing immunohistochemistry and quantitative PCR, we examined the relationship between AR, AMH, and FSH receptor expression in fetal, newborn, and adult human testis. The ability of testosterone to repress AMH secretion was evaluated in male newborns, neonates, and two adults with androgen insensitivity syndrome and also in vitro using SMAT1 SC.nnnRESULTSnFSH receptor was present in SC at all developmental stages. In fetal and newborn testis, AR was expressed in peritubular and Leydig cells but not in SC. This coincided with the absence of spermatogenesis and with strong SC AMH expression. In adult testis, spermatogenesis was associated with AR expression and with a decrease in SC AMH content. Accordingly, AR mRNA expression was lower and AMH mRNA expression higher in fetal testes than in adult testes. In androgen insensitivity syndrome patients, combined gonadotropin stimulation induced an increase in circulating testosterone and AMH, a finding consistent with a failure of TT to repress AMH in the absence of AR signalling. Finally, direct androgen repression of AMH only occurred in AR-expressing SMAT1 cells.nnnCONCLUSIONnFunctional ARs are essential for TT-mediated AMH repression in SC.

Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure

OBJECTIVEnPremature ovarian failure (POF) encompasses a heterogeneous spectrum of conditions, with phenotypic variability among patients. The etiology of POF remains unknown in most cases. We performed a global phenotyping of POF women with the aim of better orienting attempts at an etiological diagnosis.nnnDESIGN AND METHODSnWe performed a mixed retrospective and prospective study of clinical, biological, histological, morphological, and genetic data relating to 357 consecutive POF patients between 1997 and 2008. The study was conducted at a reproductive endocrinology referral center.nnnRESULTSnSeventy-six percent of the patients presented with normal puberty and secondary amenorrhea. Family history was present in 14% of the patients, clinical and/or biological autoimmunity in 14.3%. Fifty-six women had a fluctuating form of POF. The presence of follicles was suggested at ultrasonography in 50% of the patients, and observed in 29% at histology; the negative predictive value of the presence of follicles at ultrasonography was 77%. Bone mineral density alterations were found in 58% of the women. Eight patients had X chromosomal abnormalities other than Turners syndrome, eight other patients evidenced FMR1 pre-mutation. Two other patients had autoimmune polyendocrine syndrome type 2 and 1.nnnCONCLUSIONnA genetic cause of POF was identified in 25 patients, i.e. 7% of the whole cohort. POF etiology remains most often undiscovered. Novel strategies of POF phenotyping are in such content mandatory to improve the rate of POF patients for whom etiology is identified.

Sperm parameters and male fertility after bariatric surgery: three case series

Recent studies have underlined the impact of obesity on sperm parameters, but very few data are available on the effect of weight loss on male fertility. This article reports the case series of three male patients who underwent rapid and major weight loss following bariatric surgery and the consequences of this surgery on semen parameters and fertility. A severe worsening of semen parameters was observed during the months after bariatric surgery, including extreme oligoasthenoteratozoospermia, but azoospermia was not observed. This effect may hypothetically be the result of two opposite mechanisms: (i) the suppression of the deleterious effects of obesity; and (ii) the negative impact of both nutritional deficiencies and the release of toxic substances. Information about potential reproductive consequences of bariatric surgery should be given to patients and sperm cryopreservation before surgery proposed. However, for one case, the alterations of spermatogenesis were reversible 2 years after the surgical procedure. Finally, intracytoplasmic sperm injection with fresh spermatozoa after male bariatric surgery can be successful, as demonstrated here, where clinical pregnancies were obtained for two out of the three couples.

Age and ovarian reserve are distinct predictive factors of cycle outcome in low responders.

The respective roles of age and ovarian reserve in predicting IVF outcome do not seem to be equivalent, as a high pregnancy rate seems to be preserved in the youngest women, despite low ovarian recruitment. The purpose of this study was to analyse the outcome of IVF/intracytoplasmic sperm injection (ICSI) procedures according to both age and ovarian reserve of patients with a low ovarian response to stimulation. A total of 163 IVF/ICSI cycles selected by a low response were analysed. The IVF outcome differed according to the womens age, with a cut-off value at 36 years. While the number of transferred embryos was similar, the pregnancy rate (PR) was 14.6% in younger patients but 4.9% (P < 0.04) in older ones. An elevated FSH was constantly associated with a poor cycle outcome. In contrast, when the FSH was normal, PR was significantly higher (P < 0.05) in women aged <36 (23.8%) than in women aged > or =36 (6.5%). This study shows that assisted reproduction outcome in women with a low ovarian response is primarily dependent on the ovarian status. The negative influence of age is relevant in patients with normal FSH. Therefore, even if the ovarian response to stimulation is low, patients aged <36 years with a normal FSH should proceed to oocyte retrieval.

New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF

BACKGROUNDnThe advent of embryo and oocyte vitrification today gives reproductive specialists an opportunity to consider new strategies for improving the practice and results of IVF attempts. As the freezing of entire cohorts does not compromise, and may even improve, the results of IVF attempts, it is possible to break away from the standard sequence of stimulation-retrieval-transfer. The constraints associated with ovarian stimulation in relation to the potential harmful effects of the hormonal environment on endometrial receptivity can be avoided.nnnOBJECTIVE AND RATIONALEnThis review will look at the new stimulation protocols where progesterone is used to block the LH surge. Thanks to freeze all strategies, the increase in progesterone could actually be no longer a cause for concern. There are two ways of using progesterone, whether it be endogenous, as in luteal phase stimulation, or exogenous, as in the use of progesterone in the follicular phase i.e. progestin primed ovarian stimulation.nnnSEARCH METHODSnA literature search was carried out (until September 2016) on MEDLINE. The following text words were utilized to generate the list of citations: progestin primed ovarian stimulation, luteal phase stimulation, luteal stimulation, duostim, double stimulation, random start. Articles and their references were then examined in order to identify other potential studies. All of the articles are reported in this review.nnnOUTCOMESnThe use of progesterone during ovarian stimulation is effective in blocking the LH surge, whether endogenous or exogenous, and it does not affect the number of oocytes collected or the quality of the embryos obtained. Its main constraint is that it requires total freezing and delayed transfer. A variety of stimulation protocols can be derived from these two methods, and their implications are discussed, from fertility preservation to ovarian response profiles to organization for the patients and clincs. These new regimens enable more flexibility and are of emerging interest in daily practice. However, their medical and economic significance remains to be demonstrated.nnnWIDER IMPLICATIONSnThe use of luteal phase or follicular phase protocols with progestins could rapidly develop in the context of oocyte donation and fertility preservation not related to oncology. Their place could develop even more in the general population of patients in IVF programs. The strategy of total freezing continues to develop, thanks to technical improvements, in particular vitrification and PGS on blastocysts, and thanks to studies showing improvements in embryo implantation when the transfer take place far removed from the hormonal changes caused by ovarian stimulation.

Healthy birth after testicular extraction of sperm and ICSI from an azoospermic man with mild androgen insensitivity syndrome caused by an androgen receptor partial loss-of-function mutation.

The androgen receptor (AR) is essential for the development and maintenance of the male phenotype, and for spermatogenesis. Mutations in the AR gene cause a wide variety of androgen insensitivity syndromes (AIS), ranging from complete feminization to phenotypic males with infertility.

Proximal occlusion of hydrosalpinges by Essure® before assisted reproduction techniques: a French survey

OBJECTIVESnTo study the feasibility and results (live-birth and complication rates) of placement of Essure(®) microinserts before assisted reproductive technology (ART) treatment of women with hydrosalpinx when laparoscopy should be avoided. Study design National survey of 45 French hospital centres providing ART reporting a retrospective analysis of 43 women with unilateral or bilateral hydrosalpinges and Essure(®) placement. The results of the following ART cycle were studied for 54 embryo transfers.nnnRESULTSnThe placement success rate reached 92.8% (65/70 tubes), and the mean number of visible intrauterine coils was 1.61 (range: 0-6). Pyosalpinx occurred in one case, and expulsion of the device into the uterus in two others. Of 43 women, 29 (67.4%) had a total of 54 fresh or frozen embryos transferred. The clinical pregnancy rate was 40.7% (22/54) and the live-birth rate 25.9% (14/54). The implantation rate was 29.3% (27/92).nnnCONCLUSIONnEssure(®) placement is an effective method for occlusion of hydrosalpinges before IVF. Monitoring the live-birth rate confirms that this option is the strongest in cases when laparoscopy is impossible or contraindicated.

Beneficial effects of GnRH agonist administration prior to ovarian stimulation for patients with a short follicular phase

A short follicular phase is an early clinical feature of declining reproductive competence. The shortening of the follicular phase length is related to both advanced recruitment and selection of the dominant follicle secondary to an earlier and higher FSH rise during the luteal-follicular transition, while the late follicular growth is normal. As a short follicular phase may be detrimental for reproduction, it was postulated that increasing the duration of follicular phase could improve conception rate. For that purpose, gonadotrophin-releasing hormone agonist minidoses were administered in the mid-luteal phase to prevent the intercycle FSH rise before tailoring follicular growth by controlled exogenous FSH administration. This regimen, applied to 69 infertile ovulatory women with a short follicular phase (9.6 +/- 1.2 days) actually lengthened the follicular phase by about 3 days. It proved to be effective in 179 cycles to induce paucifollicular development (1.8 +/- 0.9 follicles) with a low cancellation rate (4%) and a moderate requirement for gonadotrophins [13.3 +/- 6.3 ampoules (75 IU)]. In those women with a high frequency (80%) of elevated basal FSH or oestradiol concentrations, the pregnancy rate reached 15.1%/cycle but the miscarriage rate remained high (44%). Thus, increasing the follicular phase length in patients with a short follicular phase may partially restore fecundity.

Faut-il traiter par metformine les femmes infertiles présentant un syndrome des ovaires polykystiques ?

Resume Le syndrome des ovaires polykystiques est souvent associe a une insulino-resistance et une hyperinsulinemie qui jouent un role probable dans l’hyperandrogenie et l’anovulation. L’utilisation d’agents « insulino-sensibilisants » a ete proposee pour reduire l’insulino-resistance et l’hyperandrogenie. Cette revue fait le point sur l’utilisation de la metformine dans cette indication. Bien que son mecanisme d’action ne soit pas univoque, la metformine semble efficace pour retablir la cyclicite voire l’ovulation spontanee. Son effet potentialisateur de l’action du citrate de clomifene a ete mis en evidence dans certaines etudes et elle pourrait etre consideree comme un adjuvant utile dans les cas de resistance. Cependant, la reduction du risque d’hyperstimulation chez les patientes traitees par FSH exogene necessite d’etre confirmee au meme titre que son effet benefique potentiel pour diminuer le risque de fausses couches precoces. Nous proposons une strategie d’utilisation de la metformine comme traitement adjuvant pour retablir la cyclicite et l’ovulation dans le SOPK.

Anti-Müllerian Hormone and Ovarian Morphology in Women With Isolated Hypogonadotropic Hypogonadism/Kallmann Syndrome: Effects of Recombinant Human FSH

ContextnIsolated hypogonadotropic hypogonadism (IHH), characterized by gonadotropin deficiency and absent puberty, is very rare in women. IHH prevents pubertal ovarian stimulation, but anti-Müllerian hormone (AMH) and antral follicle count (AFC) have not been studied.nnnObjectivesn(1) To compare, in IHH vs controls, AMH, ovarian volume (OV), and AFC. (2) To compare, in IHH, ovarian responses to recombinant human follicle-stimulating hormone (rhFSH) and rhFSH plus recombinant human luteinizing hormone (rhLH).nnnSubjectsnSixty-eight IHH women; 51 matched healthy women.nnnMethodsnSerum LH, FSH, sex steroids, inhibin B (InhB), AMH, and OV and AFC (sonography) were compared. Ovarian response during rhFSH administration was assessed in 12 IHH women with low AMH levels and low AFC and compared with hormonal changes observed in six additional IHH women receiving rhFSH plus rhLH.nnnResultsnInhB was lower in IHH than in controls. AMH levels were also significantly lower in the patients, but two-thirds had normal values. Mean OV and total, larger, and smaller AFCs were lower in IHH than in controls. Ovarian stimulation by rhFSH led to a significant increase in serum estradiol and InhB levels and in the number of larger antral follicles. AMH and smaller AFC increased early during rhFSH stimulation but then declined despite continued stimulation. rhFSH plus rhLH stimulation led to a significantly higher increase in estradiol levels but to similar changes in circulating InhB and AMH than with rhFSH alone.nnnConclusionsnIHH women have both low AMH levels and low AFC. However, their decrease can be reversed by follicle-stimulating hormone. Serum AMH and AFC should not serve as prognostic markers of fertility in this population.