Subfertility (or infertility) is generally defined as the inability to conceive after 12 months of regular, unprotected intercourse. A clinical approach to subfertility requires an understanding of its major causes:

• Unexplained: 28%
• Male factors: 24%
• Ovarian dysfunction (Anovulation): 21%
• Tubal factors: 14%
• Other causes: 13%

Reference: Jose-Miller AB, et al. Am Fam Physician 2007;75:849-56, 857-8.

Preconception care is a broad term that refers to the process of identifying social, behavioral, environmental, and biomedical risks to a woman's fertility and pregnancy outcome, and then reducing these risks through education, counseling, and appropriate intervention.

• BMI (Body Mass Index): Counseling on weight optimization (weight loss for obese patients is a primary strategy to restore ovulatory cycles).
• BP (Blood Pressure): Monitoring and optimization of cardiovascular health.
• Lifestyle Counseling: Smoking cessation, reducing alcohol intake, managing stress, and maintaining a healthy diet.
• Garbh Sanskar / Spiritual: Mental and spiritual preparation for pregnancy to reduce maternal stress.
• Folic Acid Supplementation: To prevent neural tube defects.
• Anemia Correction: Screening and treating iron-deficiency or other forms of anemia.
• Sugar / Thyroid: Strict glycemic control for diabetics and optimization of TSH levels.
• Correction of Endocrine Factors: Addressing underlying hormonal imbalances (e.g., hyperprolactinemia).
• Thalassemia Screen: Genetic screening wherever indicated.

• FOGSI recommends vaccination counseling as a part of pre-pregnancy counseling (for unvaccinated women).
• History of occurrence of vaccine-preventable diseases, previous vaccinations administered, and allergic reactions to vaccinations must be recorded.
• Rubella, Hepatitis B, and Varicella vaccination should be given, preferably during the postmenstrual period.
• Pregnancy should be deferred for 3 months in the case of the Rubella vaccine.

Ovulation induction is the method for treating anovulatory infertility. The clinical approach requires an understanding of the causes of anovulation. Goals of ovulation induction include inducing mono-follicular rather than multi-follicular development, leading to mono-ovulation, a singleton pregnancy, and the birth of a healthy newborn.

Historically, The World Health Organization (WHO) categorized ovulation disorders into three groups. Patients eligible for ovulation induction belong either to WHO group I or to WHO group II.

Most experts have moved away from the strict WHO terminology. The modern approach focuses on the specific pathology:

1. Polycystic Ovary Syndrome (PCOS)
   • Corresponds to WHO Class 2. This is the most common cause of anovulation.
   • Almost all women in this category have PCOS when using the Rotterdam criteria for diagnosis.
   • Treatment Approach:
     • First-line: Letrozole (superior to clomiphene, especially in restoring ovulation and improving live-birth rates regardless of BMI) or Clomiphene citrate. Weight loss and lifestyle changes (Grade 2B recommendation).
     • Second-line: Gonadotropin injections (FSH) or Laparoscopic Ovarian Diathermy (ovarian drilling) using electrocautery or laser.
     • Third-line: In Vitro Fertilization (IVF).
2. Hypogonadotropic Hypogonadism (HA)
   • Corresponds to WHO Class 1.
   • Hypothalamic causes include functional hypothalamic amenorrhea (FHA) and isolated gonadotropin-releasing hormone (GnRH) deficiency.
   • Multiple factors contribute to FHA: eating disorders (anorexia nervosa), excessive exercise, and stress.
   • Rarely, it presents as primary amenorrhea due to complete congenital GnRH deficiency (Idiopathic hypogonadotropic hypogonadism, or Kallmann syndrome if associated with anosmia).
   • Infiltrative diseases and tumors of the hypothalamus/pituitary can also cause it due to diminished GnRH or gonadotropin release.
3. Primary Ovarian Insufficiency (POI)
   • Corresponds to WHO Class 3. Formerly referred to as premature ovarian failure (POF).
   • Defined as menopause before age 40 years. Occurs in only 1% of all women but accounts for 5-10% of cases of anovulation.
   • In most cases, the follicle pool is exhausted due to accelerated follicle loss of unknown origin.
   • The only effective fertility option is IVF with donor oocytes. No ovulation induction strategy has been shown to be effective.
   • Women with POI have other health issues related to estrogen deficiency, including an increased risk of osteoporosis and cardiovascular disease if estrogen is not replaced.
4. Hyperprolactinemia
   • Did not have a separate WHO category. Accounts for 5 to 10% of women with anovulation.
   • Hyperprolactinemia inhibits gonadotropin secretion, presumably by inhibiting GnRH.
   • Most patients have oligomenorrhea or amenorrhea. Serum gonadotropin concentrations are usually normal or decreased.
   • Treatment: Ovulation induction with dopamine agonists (Bromocriptine or Cabergoline) (Grade 2C).

Gonadotropins are a class of fertility medications given by injection that contain follicle-stimulating hormone (FSH) alone or combined with luteinizing hormone (LH). They stimulate the gonads (ovaries in females, testes in males) and are regulated by the hypothalamus via GnRH.

Since their introduction in 1961, various formulations have been used. Evidence indicates no significant difference in effectiveness (clinical pregnancy or live-birth rates) or OHSS rates between different preparations (Cochrane Database 2015).

• hMG (Human Menopausal Gonadotropins): Extracted from the urine of postmenopausal women. The ratio of LH to FSH bioactivity is 1:1 (e.g., Pergonal, Humegon).
• Highly Purified hMG (HP-hMG)
• Urinary FSH (uFSH): Refinement of the crude preparation to isolate FSH. Purified uFSH has some LH activity.
• Recombinant human FSH (rhFSH): Available since 1996, >99% purity. Does not contain LH activity. Appealing due to ease of subcutaneous administration and batch-to-batch consistency. *Note: Long-acting rhFSH is registered for IVF but not advised for basic ovulation induction.*

Clinical Note: Women with hypogonadotropic hypogonadism who have very low serum LH (<0.5 IU/L) need exogenous hCG or recombinant LH alongside rhFSH to maintain adequate estradiol biosynthesis and follicle development.

• Women with PCOS who have not ovulated or conceived with weight loss, clomiphene, or letrozole therapy (second-line).
• Hypogonadotropic anovulatory women with hypopituitarism or hypothalamic amenorrhea (HA) who do not have access to pulsatile GnRH therapy.
• Used to stimulate multiple follicle development for harvesting ova in IVF.
• Used to stimulate spermatogenesis in men with low sperm counts and normal functioning testes.

Because ovarian sensitivity to FSH varies, specific protocols are needed to achieve the formation of a single dominant follicle and avoid multiple pregnancies/OHSS. The starting dose depends on Age, Antral Follicle Count, AMH, and previous response.

Starting dose of FSH is 150 IU/day. However, this regimen is associated with an unacceptably high multiple pregnancy rate (up to 36%) and Ovarian Hyperstimulation Syndrome (OHSS) (up to 14%). It has largely been abandoned for PCOS patients.

Designed to allow the FSH threshold to be reached gradually, minimizing excessive stimulation.

• Initial SC or IM dose of FSH is 37.5 to 75 IU/day.
• The dose is increased only if, after 14 days, no response is documented on ultrasonography and serum estradiol monitoring.
• Increments of 37.5 IU are given at weekly intervals up to a maximum of 225 IU/day.
• Detection of an ovarian response is an indication to continue the current dose until hCG can be given to stimulate ovulation.

Mimics normal physiological cycles more closely.

• Therapy with 150 IU FSH/day is started shortly after spontaneous or progesterone-induced bleeding.
• Continued until a dominant follicle (>10 mm) is seen on TVS.
• The dose is then decreased to 112.5 IU/day, followed by a further decrease to 75 IU/day three days later.
• Continued until hCG is administered. (Robustness in everyday practice remains evaluated; step-up is preferred first).

Advantages of CC + Gonadotropins: Higher pregnancy rate than CC alone, more cost-effective, lesser multiple pregnancy rate than gonadotropins alone, lower incidence of OHSS compared to conventional regimes.
Disadvantages: Anti-estrogenic effect of CC on the endometrium.
Letrozole + Gonadotropins: Used to reduce the requirement of gonadotropins and side effects. However, some studies found slightly lower pregnancy rates compared to FSH alone.

• Transvaginal Ultrasound (TVS): The primary tool to monitor follicular diameter (number & size) and the pattern/thickness of the endometrium. Baseline D2 scan is performed. Scans in the late follicular phase are done every 2-3 days.
• Serum Estradiol: Measurements are useful; preovulatory concentrations above normal ranges may predict OHSS.
• Serum Progesterone: Sometimes useful before hCG to determine if a premature LH surge has occurred (routine measurement not suggested).
• Dose Adjustments (IUI Cycle):
  • Lead follicle >10mm, 2-3 follicles: Keep same dose.
  • 4-6 follicles: Keep same dose or taper.
  • >6 follicles: Taper and look for OHSS.
  • Lead follicle <10mm: Increase the dose.

hCG acts as a surrogate for the natural LH surge to induce final oocyte maturation and ovulation.

• When to give: Administered on the day at least one follicle appears mature.
  • HCG at 18-20 mm (CC + Gonadotropin cycles).
  • HCG at 20-22 mm (CC alone cycles).
• Dose: 5000 - 10,000 IU of urinary hCG, OR 250 mcg of recombinant hCG (Ovidrel).
• Withholding Trigger: Strict attention to follicle number is essential. To minimize the risk of multiple gestation and OHSS, if three or more follicles >15 mm are present, or serum estradiol is extremely high, stimulation should be stopped, hCG withheld, and barrier contraception advised.

• GnRH Agonists: Used to avoid interference from endogenous gonadotropin secretion. However, use of GnRH analogues in standard IUI cycles is not recommended as they do not significantly improve pregnancy rates.
• GnRH Antagonists (Cetrorelix, Ganirelix): Indicated for conversion of IUI to IVF cycles (flexibility) and programming to avoid weekends. However, Cochrane reviews concluded antagonists were not helpful in improving pregnancy rates for basic IUI. Protocols:
  • Lubeck Protocol: Antagonist started when follicle reaches 14mm, or from day 6 of stimulation (0.25mg/day until hCG injection).
  • French Protocol: Single 3mg dose of antagonist given when E2 is 150-200 pg/ml and follicle is 14mm.

The risk of multiple gestation is increased with clomiphene, but to a much greater extent with gonadotropin therapy. Adherence to low-dose protocols and strict trigger-withholding criteria is required.

OHSS is a potentially life-threatening complication of ovulation induction caused by excessive ovarian stimulation. It leads to massive fluid shifts from the intravascular space to the third space due to increased vascular permeability.

• Mild/Moderate: Abdominal pain, bloating, distention, nausea, diarrhea, ovarian enlargement. Managed with OPD care.
• Severe: Ascites, pleural effusion, severe hemoconcentration, oliguria, thromboembolism. Requires In-patient care or ICU admission.

• Ovarian Cancer: Early studies suggested an association with borderline ovarian tumors. However, best evidence (systematic review of 11 case-control and 14 cohort studies of 182,972 women) shows no convincing evidence of an excess risk of invasive ovarian tumors with fertility drug therapy. Infertility itself is an independent risk factor. Note: Due to one study suggesting increased risk, women should generally not receive more than 12 cycles of clomiphene citrate.
• Breast Cancer: There does not appear to be an increased risk of breast cancer in women treated with fertility drugs. In a prospective cohort, women who used fertility drugs and conceived had the same risk as non-users.
• Other Cancers: No association found with melanoma, thyroid, cervical, or colon cancers.

A large population-based study found that childhood tumor risk was not increased. Congenital malformation risk does not appear to be increased with oral ovulation induction agents, though ongoing monitoring is warranted.

Gonadotropin therapy following CC failure is the classical approach. Cumulative singleton live-birth rates of 71% over 24 months have been reported, confirming it as an effective means before proceeding to IVF. Success rates are negatively influenced by age, obesity, and insulin resistance.

Luteal phase support is utilized to ensure the endometrium is receptive for implantation.

• Required: Definitely required when using Gonadotropins AND GnRH analogs (Agonist or Antagonist). Supported by meta-analysis showing distinct clinical benefit.
• Empirical: Often given empirically in most Letrozole and CC cycles, although meta-analyses show no significant benefit for CC alone (benefit is seen in CC + Gonadotropin cycles).

• Progesterone: Administered via different routes: oral, intramuscular, or vaginal (suppositories/gels).
• Dydrogesterone: Structurally and pharmacologically similar to natural progesterone. Has good oral bioavailability, a good safety and tolerability profile, and crucially, no androgenic effects on the fetus.

Early referral benefits include a reasonable chance of achieving pregnancy, an increase in live birth rate, and a reduction in recurrent pregnancy loss.

• Unexplained Infertility (Idiopathic): IVF is the method of choice if the duration of infertility is 3 years or longer. If the woman is older than 36 years, IVF may be considered earlier. (IUI merits consideration before IVF).
• Hormonal Disturbances: IVF is the method of choice in case of anovulatory cycle abnormalities if 12 cycles of treatment with ovulation induction have been unsuccessful.

Drugs that affect the female reproductive system typically include Female Sex Hormones, Estrogen Receptor Modulators, Fertility Drugs (Gonadotropins), Uterotonics, and Abortifacients.

Used for hormone replacement therapy (HRT), oral contraceptives, treating hypogonadism, endometriosis, dysmenorrhea, and palliative cancer care.

• Functions: Stimulates development of female sex characteristics, thickens endometrial lining, maintains bone mineral density, prevents atherosclerosis (increases HDL, lowers LDL), and maintains vaginal lubrication/libido.
• Dosages:
  • Estradiol: 1–2 mg/day orally, or 1–5 mg IM every 3–4 weeks, or 2–4 g intravaginal cream daily.
  • Conjugated Estrogens (Premarin): 0.3–1.25 mg/day orally.
• Contraindications: Idiopathic vaginal bleeding, estrogen-dependent cancers (Breast Cancer), History of CVA/Thromboembolism (increases clotting factors), Hepatic dysfunction, Pregnancy, Lactation.
• Drug Interactions:
  • Barbiturates, rifampin, tetracyclines, phenytoin: Decrease serum estrogen levels.
  • Grapefruit juice & St. John’s wort: Inhibit metabolism, altering effectiveness.
  • Nicotine: Drastically increases risk of thrombi and emboli.

• Functions: The "pregnancy hormone". Transforms proliferative endometrium into secretory endometrium. Prevents uterine contractions. Inhibits GnRH, FSH, and LH in contraceptives.
• Dosages:
  • Etonogestrel (Implanon): 68 mg implanted sub-dermally for up to 3 years.
  • Medroxyprogesterone (Provera): 5–10 mg/day PO for 5–10 days (amenorrhea) or 150 mg deep IM every 3 months for contraception.
• Contraindications: PID, STD, Endometriosis, Hepatic/Renal disorders, Epilepsy, Asthma, Migraines (can exacerbate fluid retention).

General Adverse Effects of Female Sex Hormones: Peripheral edema, chloasma, nausea, vomiting, bloating, withdrawal bleeding, hepatic adenoma, photosensitivity, corneal changes.

• Contraindications: Primary ovarian failure (drugs need functioning ovaries to work), Undiagnosed uterine bleeding, Ovarian cysts (drugs will exacerbate them), Pregnancy, Thromboembolic disease, Uncontrolled thyroid/adrenal dysfunction.
• Adverse Effects:
  • Ovarian Hyperstimulation Syndrome (OHSS): Abdominal pain, ascites, pleural effusion.
  • Multiple Gestations: Greatly increased risk.
  • Fluid Retention: Common due to high estrogen levels promoting sodium retention, and increased pelvic blood flow.
  • Others: Headache, nausea, bloating, visual disturbances (especially with Clomiphene - indicates immediate cessation), gynecomastia (in men), and febrile reactions.

• Women receiving reproductive hormones should receive an annual medical examination, including breast examination and Pap smear.
• Drugs used in the treatment of specific cancers in males (like estrogens for prostate cancer) require education about the possibility of estrogenic effects (gynecomastia).
• Not indicated during pregnancy or lactation due to fetal risks. Always rule out pregnancy before starting a new cycle of ovulation induction.

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