A missed Nobel: Dr Subhas Mukhopadhyay (1931-1981), the Father of Indian IVF.

The Indian journey of assisted reproductive therapy began in Calcutta on 3 October 1978, when Dr Subhas Mukhopadhyay discovered the technique of in vitro fertilisation (IVF) only 67 days following the birth of the world's first IVF baby, Louise Brown in the United Kingdom by Edwards and Steptoe. While Edwards won the Nobel Prize in 2010 for his groundbreaking work, Mukhopadhyay, the man behind the genesis of 'Durga', India's first IVF baby, never received any recognition. Instead, he faced severe humiliation from his peers. His colleagues and the government dismissed his claims and unable to live with dishonour and disgrace, he tragically took his life on 19 June 1981. Today his innovative techniques of cryopreservation, gonadotropin stimulation and transvaginal oocyte retrieval are used worldwide across millions of fertility clinics, helping childless couples live the dream of parenthood.

Impact of antioxidants in improving semen parameters like count, motility and DNA fragmentation in sub-fertile males: a randomized, double-blind, placebo-controlled clinical trial.

Male infertility is solely responsible for 20-30% of infertility cases. Oxidative damage of sperm DNA is positively linked with oligoasthenoteratozoospermia (OAT), and male infertility. The antioxidants are being explored worldwide to combat OAT, sperm DNA fragmentation and reactive oxygen species. The objective of the study was to assess the effectiveness of an antioxidant blend in improving sperm count, semen parameters and reducing DNA fragmentation index (DFI) in sub-fertile males. A prospective, double-blind, randomized, placebo-controlled trial was conducted in 300 sub-fertile males (25-45 years) from ten study sites in India. Subjects were randomized in either the antioxidant blend treatment group or placebo group. We assessed changes in sperm count, motility, normal morphology, semen volume, and percent DFI before and after treatment (90 days). To further stratify data on different criteria post hoc analysis was performed. Statistical analysis was performed using SPSS 10.0 software. There were improvements in sperm count, semen volume, sperm motility, and sperm normal morphology in the treatment group. There was improvement in sperm count in severe oligospermia subjects (sperm count < 5 million/mL, 5-10 million/mL, 10.1-15 million/mL), and high-extremely higher baseline DFI (20-30%, 31-40% and above 40%), as per post hoc analysis. There was no premature discontinuation and adverse events were reported during the study, indicating safety and well-tolerability of treatment. Study results confirmed the well-researched fact of antioxidants being effective to reduce oxidative stress and thus improve sperm DNA integrity and also improved semen parameters in males aged 40 and above. Trial Registration: Clinical Trials Registry-India Identifier: CTRI/2020/12/029590.

Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles.

Progesterone elevation (PE) during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF)/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i) Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii) Is PE on the day of human chorionic gonadotropin (hCG) associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI) cycles outcomes in all patient subgroups? (iii) Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv) Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle-stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the limitations of the currently available assays to measure progesterone at low ranges, caution should be applied to adopt specific cutoff values above which the effect of progesterone rise could be considered detrimental and to recommend "freeze-all" based solely on pre-defined cutoff points.

A longitudinal study of the effect of subcutaneous estrogen replacement on bone in young women with Turner's syndrome.

It is desirable that young women with primary ovarian failure achieve normal peak bone mass to reduce the subsequent risk of osteoporosis, and that there are management strategies to replace bone that is already lost. While estrogen (E2) is generally considered to prevent bone loss by suppressing bone resorption, it is now recognized that estrogen also exerts an anabolic effect on the human skeleton. In this study, we tested whether estrogen could increase bone mass in women with primary ovarian failure. We studied the mechanism underlying this by analyzing biochemical markers of bone turnover and iliac crest biopsy specimens obtained before and 3 years after E2 replacement. Twenty-one women with Turner's syndrome, aged 20-40 years, were studied. The T scores of bone mineral density at lumbar spine and proximal femur at baseline were -1.4 and -1.1, respectively. Hormone replacement was given as subcutaneous E2 implants (50 mg every 6 months) with oral medroxy progesterone. Serum E2 levels increased incrementally from 87.5 pM at baseline to 323, 506, 647, and 713 pM after 6 months and 1, 2, and 3 years of hormone replacement therapy (HRT), respectively. The bone mineral density at the lumbar spine and proximal femur increased after 3 years to T scores of -0.2 and -0.4, respectively. The cancellous bone volume increased significantly from 13.4% to 18.8%. There was a decrease in activation frequency, but the active formation period was increased by HRT. There was a significant increase in the wall thickness from 33.4 microm at baseline to 40.9 microm after 3 years of HRT, reflecting an increase in bone formed at individual remodeling units. Although there was an early increase in biochemical markers of bone formation, these declined thereafter. Our results show that estrogen is capable of exerting an anabolic effect in the skeleton of young women with Turner's syndrome and low bone mass.

An effective alternative to only gonadotrophin for controlled ovarian stimulation in unexplained infertility patients undergoing intra-uterine insemination: a clinical trial.

Clomiphene citrate, by stimulating the endogenous gonadotrophin secretion, reduces the dose of exogenous gonadotrophin for controlled ovarian stimulation. However, the benefit of clomiphene citrate may be offset by its oestrogen-receptor depleting effect on target tissues like endometrium. Letrozole, an aromatase inhibitor, stimulates endogenous gonadotrophin secretion (like clomiphene citrate). However, it does not deplete oestrogen receptors and hence does not have adverse effect on endometrium (unlike clomiphene citrate). To evaluate the effectiveness of letrozole + FSH combination versus only FSH for contolled ovarian stimulation in unexplained infertility patients undergoing intra-uterine insemination, a prospective randomised trial was undertaken among 55 patients with unexplained infertility completed all together 118 treatment cycles of controlled ovarian stimulation and intra-uterine insemination. All these patients were regularly ovulatory women and had folliculometry by transvaginal ultrasound scanning (without any medication) with timed intercourse for Initial 2 cycles before going for controlled ovarian stimulation and intra-uterine insemination. Thereafter, 29 patients, of these 55 patients, who were allotted to one group (letrozole + FSH group) started the treatment cycle of controlled ovarian stimulation and intrauterine insemination. For controlled ovarian stimulation, each of these 29 patients received letrozole 2.5 mg from day 3 to day 7. From day 7 onwards, each patient received FSH injection intramuscular (50-150 IU/day) until the leading follicle is > or = 18 mm. Twenty-six patients, of these 55 patients, were allotted to another group (only FSH group). Each of these patients received FSH injection intramuscular (50-225 units/day) from day 3 until the leading follicle is > or = 18 mm. Monitoring of follicular development was done by transvaginal ultrasound scan, first on day 2/3 of each treatment cycle, then on day 7 and thereafter on alternate day or sometimes on successive days till the leading follicle is 18 mm or more. The dose and duration of FSH was adjusted depending on the number and size of growing follicles. Injection hCG 10000 units intramuscular was administered when the leading follicle was 18 mm or more. Intra-uterine insemination was performed 36 hours following hCG administration. Urine for pregnancy test was performed 21 days later if the patient did not have period by then. In each group, the outcome measures noted are mean of total dose of FSH/cycle, total number of mature follicles (> 16 mm) (on the day of hCG administration), endometrial thickness (on the day of hCG administration), and pregnancy rate/cycle. Statistical analysis was carried by using unpaired 't' test on continuous variables whereas Fisher's exact test was used on categorical variables. There was no significant difference in mean of total number of mature follicles (> 16 mm) and endometrial thickness on the day of hCG administration as well as pregnancy rate/cycle between two groups. However, the mean total dose of FSH/cycle and mean total duration of FSH administration/cycle were significantly less in letrozole + FSH group compared with only FSH group.