Comprehensive diagnostic and therapeutic approach to male factor infertility aimed at natural fertility: A multicentric retrospective cohort study

Giuseppe Grande; Andrea Garolla; Andrea Graziani; Anna Laura Astorri; Maria Vittoria Cammarota; Annamaria Merola; Maria Pia Polidori; Emanuela Lulli; Enrico Busato; Francesco Pesce; Giuseppina Pompa; Alfredo Pontecorvi; Domenico Milardi; Alberto Ferlin

doi:10.1111/andr.70006

Male Fertility · Male Factor Treatment

Comprehensive diagnostic and therapeutic approach to male factor infertility aimed at natural fertility: A multicentric retrospective cohort study

Grande G, Garolla A, Graziani A, Astorri AL, Cammarota MV, Merola A, Polidori MP, Lulli E, Busato E, Pesce F, Pompa G, Pontecorvi A, Milardi D, Ferlin A

Published November 2025 Andrology, 13(8), 2122-2130

DOI 10.1111/andr.70006 PMID 39930939 PMC PMC12569740

RRM Academy Synopsis

Full workup of both partners cut unexplained infertility to 8%

A full workup of both partners left only 8% of couples with unexplained infertility. The retrospective cohort had 1,014 Italian couples who refused ART. Pregnancy without ART followed targeted treatment in about 4 out of 10 treated couples. Rates fell with the woman's age.

Key Findings

An isolated male factor was found in 233 of 1,014 couples (23%), and male and female factors together in 456 (45%). Unexplained infertility remained in 82 couples (8%).
Of 919 treated couples, 376 (40.9%) became pregnant spontaneously. By female age: 53.73% under 34, 34.30% at 35-39, 14.78% at 40-42, and 3.83% over 43.
In 209 treated couples with isolated male factor, 68 (32.5%) became pregnant spontaneously: 47.8% with infection, 25.0% with varicocele, 17.6% with abacterial inflammation, 17.1% with hypospermatogenesis.
Spontaneous pregnancy followed in 36.1% of 266 couples with previous ART failure and 40.7% of 653 couples without it.
Among the 233 isolated male factor cases, male genital tract inflammation was found in 48.8%, infection in 43.1%, and hypospermatogenesis in 16.7%.

Interpretation

The study is a retrospective cohort from centers oriented toward natural reproductive medicine, and every couple had signed consent refusing ART. The group was self-selected. No comparison group was referred straight to ART, so the design cannot show that treatment caused the pregnancies. Follow-up lasted at least 12 months. The pregnancy rates cover the 919 treated couples. Another 95 couples had untreatable causes such as azoospermia from absent sperm production, premature ovarian failure or genetic abnormalities. Each treatment went to a different, smaller group.

RRM Context

The team examined both partners and included a fertility awareness practitioner. This follows the restorative principle of finding the cause first. Unexplained infertility means the cause is still unknown. In this cohort, the workup gave most couples a diagnosis. Male factors often appeared alongside female factors.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

In infertile couples whose male partner has alterations in semen parameters frequently, a comprehensive andrological approach is lacking and approximately 30-50% are classified as idiopathic infertility. These couples are often directly addressed to assisted reproduction techniques (ARTs). However, several clinical conditions may benefit from medical treatment. By acting on etiology and/or risk factors, this aims at improving seminal parameters and restoring natural fertility.

Objectives

To verify the impact of a comprehensive andrological assessment on the management of infertility (in particular, in couples with isolated male factor infertility) using as the primary outcome the natural pregnancy rate.

Materials and Methods

A multicenter retrospective study was conducted between 2015 and 2022 in 1014 couples with primary infertility seeking natural conception (including 266 couples with previous ART failure). Each couple underwent a multidisciplinary evaluation. This involved: a gynecologist and an andrologist both with expertise in infertility, a psychologist when requested, and a fertility awareness practitioner according to a unique diagnostic and therapeutic multidisciplinary protocol.

Results

An isolated male factor was found in 23% of couples. In 45%, it was associated with female factors also. The comprehensive diagnostic approach reduced the proportion of idiopathic infertility to 8% of the couples. Targeted treatment, based on diagnostic categories, was associated with spontaneous pregnancy in 40.9% of the couples. In the 233 cases without female factors, normal semen parameters were observed only in 13% of patients. Male genital tract inflammation was observed in 48.8% of the patients, genital tract infection in 43.1%, and hypospermatogenesis in 16.7%. Patients with infections were treated with antibiotics and probiotics. If further inflammation was documented, this was followed by low-dose corticosteroids and antioxidants. Follicle stimulating hormone (FSH) treatment was used in patients with hypospermatogenesis, and varicocele repair surgery was performed in four patients.

Discussion and Conclusions

Our data underline the efficacy of a comprehensive approach to the diagnostic process of male factor infertility, both in reducing the percentage of idiopathic infertility and in restoring natural fertility based on a targeted treatment.

Topics

Male Fertility › Male Factor Treatment › Medical Management · Infertility › Evaluation › Diagnostic Workup

Giuseppe Grande, Andrea Garolla, Andrea Graziani, Anna Laura Astorri, Maria Vittoria Cammarota, Annamaria Merola, Maria Pia Polidori, Emanuela Lulli, Enrico Busato, Francesco Pesce, Giuseppina Pompa, Alfredo Pontecorvi, Domenico Milardi, Alberto Ferlin

G Grande, A Garolla, A Graziani, A Astorri, M Cammarota, A Merola, M Polidori, E Lulli, E Busato, F Pesce, G Pompa, A Pontecorvi, D Milardi, A Ferlin

PMID 39930939 39930939 DOI 10.1111/andr.70006 10.1111/andr.70006 Grande et al. 2025, Grande 2025

Keywords

couple infertility, idiopathic infertility, male factor infertility, natural fertility, semen analysis

Comprehensive diagnostic and therapeutic approach to male factor infertility aimed at natural fertility: A multicentric retrospective cohort study

Full workup of both partners cut unexplained infertility to 8%

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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Keywords